Peptides having anti-melittin activity

ABSTRACT

Disclosed are peptides having anti-mellitin activity and having the formulae AC-IVILZZ-NH 2 , wherein Z is an amino acid. Also disclosed are compositions containing these peptides and methods of using them.

This application is a divisional of application Ser. No. 08/079,445,filed Jun. 18, 1993, now U.S. Pat. No. 5,440,016.

BACKGROUND OF THE INVENTION

This invention relates to the field of biologically active peptides and,in particular to peptides having anti-microbial activity, hemolyticactivity, anti-melittin activity or anti-enzymatic activity.

Melittin, a 26-residue peptide, is the predominant compound isolatedfrom honey bee venom (Apis mellifera). Melittin is known for its markedcytolytic activities, as well as for its allergenic properties. Earlierstudies using individual peptide analogues of melittin (Peptide Research4(1): 12-18, 1991; Biochemistry 30(19): 4671-4678, 1991), showed thatthe initial step of the mechanism of melittin's hemolytic activityinvolves interactions and/or binding between melittin and the lipidgroups of the membrane. Compounds which would inhibit these interactionsand/or bindings, would prevent the allergenic and/or lytic action ofmelittin in the bee venom. Furthermore, the generation of such acompound would give insight into the mechanism of action of melittin inits lytic activity.

Recent advances in technology have provided methods for the preparationand screening of a large mumber of individual peptides. Peptidesidentified in this manner have included peptides binding to antibodycombining sites, among other things. There is a need in the art forpeptides that have useful levels of anti-microbial activity, hemolyticactivity, anti-melittin activity or anti-enzymatic activity. Thisinvention satisfies these needs by providing such bio-active peptides.

SUMMARY OF THE INVENTION

This invention provides peptides having anti-microbial activity andhaving the formula (KFmoc)ZZZ-NH₂ SEQ ID NO: 1!, wherein Z is an aminoacid; compositions having the aforementioned peptide in an acceptablecarrier; and pharmaceutical compositions having the aforementionedpeptide in a pharmaceutically acceptable carrier wherein the peptide hasHD₅₀ greater than 100 μgms/ml. This invention also provides methods oftreating a subject having a microbial infection having the step ofadministering to the subject a therapeutically effective amount of theaforementioned pharmaceutical composition. This invention also providesmethods of inhibiting the growth of a microorganism having the step ofcontacting the microorganism with an effective amount of anaforementioned anti-microbial peptide. This invention also providesmethods of lysing red blood cells having the step of contacting redblood cells with an effective amount of an aforementioned peptide.

This invention provides compositions having a peptide havinganti-microbial activity and having the formula Ac-RRWWCZ-NH₂, wherein Zis an amino acid; compositions having the aforementioned peptide in anacceptable carrier; and pharmaceutical compositions having theaforementioned peptide wherein the peptide has HD₅₀ greater than 100μgms/ml, in a pharmaceutically acceptable carrier. This invention alsoprovides methods of treating a subject infected with a gram negativebacterium or yeast having the step of administering to the subject atherapeutically effective amount of the aforementioned pharmaceuticalcomposition. This invention provides methods of inhibiting the growth ofa gram negative bacteria or yeast having the step of contacting the gramnegative bacteria or yeast with an effective amount of theaforementioned peptide.

This invention provides anti-microbial peptides having the formulaAc-rrwwcz-NH₂, wherein z is a D-amino acid; compositions having theaforementioned peptide in an acceptable carrier; and pharmaceuticalcompositions having the aforementioned peptide in a pharmaceuticallyacceptable carrier and having HD₅₀ greater than 100 μgms/ml. Thisinvention also provides methods of treating a subject having a microbialinfection having the step of administering to the subject atherapeutically effective amount of the aforementioned pharmaceuticalcomposition, methods of inhibiting the growth of a microorganism havingthe step of contacting the microorganism with an effective amount of theaforementioned peptide; and methods of lysing red blood cells having thestep of contacting red blood cells with an effective amount of theaforementioned peptide having HD₅₀ less than 100 μgms/ml;

This invention provides peptides having anti-melittin activity andhaving the formula Ac-IVILTZ-NH₂ SEQ ID NO: 9!, Ac-IVILLZ-NH₂ SEQ ID NO:10! or Ac-IVIFFZ-NH₂ SEQ ID NO: 11!, wherein Z is an amino acid; andAc-Z₁ Z₂ IZ₃ Z₄ Z₅ -NH₂ SEQ ID NO: 12!, wherein Z₁, Z₂, Z₃, Z₄ and Z₅are amino acids; Ac-MILWIE-NH₂ SEQ ID NO: 13!, Ac-VIQQFV-NH₂ SEQ ID NO:14! and Ac-WIQIFI-NH₂ SEQ ID NO: 15!; compositions having any of theaforementioned peptides in an acceptable carrier; and pharmaceuticalcompositions having any of the aforementioned peptides in apharmaceutically acceptable carrier wherein the peptides has IC₅₀ lessthan 30 μgms/ml. This invention also provides methods of inhibitingmelittin activity having the step of contacting melittin with aneffective amount of any of the aforementioned peptides; and methods oftreating a subject suffering from melittin poisoning having the step ofadministering to the subject a therapeutically effective amount of theaforementioned pharmaceutical composition.

This invention provides peptides having the formula Ac-ryrpwz-NH₂,wherein z a D-amino acid, said peptide having an IC₅₀ less than 150 μMagainst trypsin. This invention provides methods of inhibiting trypsinactivity having the step of contacting trypsin with an effective amountof the aforementioned peptide.

DETAILED DESCRIPTION OF THIS INVENTION

This invention provides peptides having anti-microbial activity. Thesepeptides inhibit the growth of microorganisms. This invention alsoprovides peptides with high hemolytic activity. These peptides cause thelysis of red blood cells. This invention also provides peptides withanti-melittin activity. These peptides inhibit the ability of melittinto lyse red blood cells. This invention also provides peptides havinganti-trypsin activity. These peptides inhibit the protolyptic action oftrypsin. The disclosure of U.S. Pat. No. 4,631,211 is incorporatedherein by reference.

As used herein, the term "amino acid" refers both to the naturallyoccurring amino acids and their derivatives, such as TyrMe and PheCl, aswell as other moieties characterized by the presence of both availablecarboxyl group and amine group. Non-amino acid moieties which can becontained in such peptides include, for example, amino acid mimickingstructures. Mimicking structures are those structures which exhibitsubstantially the same spatial arrangement of functional groups as aminoacids but do not necessarily have both the α-amino and α-carboxyl groupscharacteristic of amino acids.

This invention provides generic peptides having a formula wherein "Z"designates an amino acid as defined above. According to certainembodiments of this invention, Z is an amino acid specified in Table 1;an L-amino acid; one of the twenty naturally occuring L-amino acids; aD-amino acid; or a D-amino acid version of one of the twenty naturallyoccuring L-amino acids.

Table 1 presents a list of amino acids referred to herein. The firstcolumn of lists abbreviations for amino acids as used in thisspecification. The second column lists amino acid abbreviations setforth in 37 C.F.R. § 1.822. The third column lists amino acids by name.

                  TABLE 1                                                         ______________________________________                                        Spec      37 C.F.R § 1.822                                               Abbreviation                                                                            Abbreviation      Name                                              ______________________________________                                        A         Ala               L-Alanine                                         R         Arg               L-Arginine                                        N         Asn               L-Asparagine                                      D         Asp               L-Aspartic                                                                    Acid                                              C         Cys               L-Cysteine                                        E         Glu               L-Glutamic                                                                    Acid                                              Q         Gln               L-Glutamine                                       G, g      Gly               Glycine                                           H         His               L-Histidine                                       I         Ile               L-Isoleucine                                      L         Leu               L-Leucine                                         K         Lys               L-Lysine                                          M         Met               L-Methionine                                      F         Phe               L-                                                                            Phenylalanine                                     P         Pro               L-Proline                                         S         Ser               L-Serine                                          T         Thr               L-Threonine                                       W         Trp               L-Tryptophan                                      Y         Tyr               L-Tyrosine                                        V         Val               L-Valine                                          Z, z      Xaa               Specified                                                                     amino acid                                        X                           Equimolar                                                                     mixture of                                                                    specified                                                                     amino acids                                       a                           D-Alanine                                         r                           D-Arginine                                        n                           D-Asparagine                                      d                           D-Aspartic                                                                    Acid                                              c                           D-Cysteine                                        e                           D-Glutamic                                                                    Acid                                              q                           D-Glutamine                                       h                           D-Histidine                                       i                           D-Isoleucine                                      l                           D-Leucine                                         k                           D-Lysine                                          m                           D-Methionine                                      f                           D-                                                                            Phenylalanine                                     p                           D-Proline                                         s                           D-Serine                                          t                           D-Threonine                                       w                           D-Tryptophan                                      y                           D-Tyrosine                                        v                           D-Valine                                          Bala      bAla              beta-alanine                                      aABA      Abu               alpha-amino                                                                   butyric acid                                      gABA      4Abu              gamma-amino                                                                   butyric acid                                      aAIB      Aib               alpha-amino                                                                   isobutyric                                                                    acid                                              eAca      Acp               epsilon-amino                                                                 caproic acid                                      bAsp                        Beta-aspartic                                                                 acid                                              gGlu                        gamma-glutamic                                                                acid                                              Cys (ACM)                   cysteine (ACM)                                    KCBZ                        epsilon-lysine                                    KFmoc                       epsilon-lysine                                                                (a-Fmoc)                                          MetO.sub.2                  methionine                                                                    sulfone                                           Nle                         norleucine                                        Nve                         norvaline                                         Orn       Orn               ornithine                                         dOrn                        delta-                                                                        ornithine                                         NO.sub.2 F                  p-nitro-                                                                      phenylalanine                                     Hyp       3Hyp              hydroxyproline                                    Thiopro                     thioproline                                       7aHa                        7-amino                                                                       heptanoic acid                                    ______________________________________                                    

As used herein, Ac- is an acetyl group of an acetylated amino-terminalamino acid of the formula: ##STR1## wherein R is the side chain.

As used herein, NH₂ is the amido group of an amidated, carboxy-terminalamino acid residue of the formula: ##STR2## where R is the side chain.

As used herein, the term "all-D-amino acid peptide" refers to a peptidecontaining only D-amino acids.

I. ANTI-MICROBIAL AND HEMOLYTIC PEPTIDES

This invention provides peptides having anti-microbial activity. As usedherein, the term "anti-microbial activity" means having IC₅₀ less than30 μgms/ml against a bacteria and IC₅₀ less than 100 μgms/ml against ayeast. More specifically, these peptides have anti-microbial activityagainst bacteria such as gram-negative bacteria (e.g., E. coli or P.aeruginosa), gram-positive bacteria (e.g., S. aureus or S. sanguis) andagainst yeast (e.g., C. albicans). Several of these peptides cosine highanti-microbial activity with low hemolytic activity. As used herein, theterm "low hemolytic activity" means having HD₅₀ (% hemolysis) greaterthan 100 μgms/ml. In one embodiment of this invention, peptides have ananti-microbial activity less than 10 μgms/ml against a bacterium oryeast.

This invention also provides peptides that find use due to their highhemolytic activity, without regard to their anti-microbial activity. Asused herein, the term "high hemolytic activity" means having HD₅₀ (%hemolysis) less than 100 μgms/ml.

A. (KFmoc)ZZZ-NH₂

This invention provides anti-microbial peptides having the generalformulae:

    ______________________________________                                        SEQUENCE ID NO:     PEPTIDE                                                   ______________________________________                                        1                   (KFmoc)ZZZ-NH.sub.2                                       2                   (KFmoc)WZZ-NH.sub.2                                       3                   (KFmoc)WKZ-NH.sub.2                                       4                   (KFmoc)WYZ-NH.sub.2                                       --                  (KFmoc)WfZ-NH.sub.2                                       --                  (KFmoc)ciZ-NH.sub.2,                                      ______________________________________                                    

wherein Z is an amino acid.

In particular, this invention provides anti-microbial peptides havingthe formula:

    ______________________________________                                        SEQUENCE ID NO:  PEPTIDE                                                      ______________________________________                                        3                (KFmoc)WKW-NH.sub.2                                          3                (KFmoc)WKC-NH.sub.2                                          3                (KFmoc)WKF-NH.sub.2                                          3                (KFmoc)WKS-NH.sub.2                                          3                (KFmoc)WKM-NH.sub.2                                          3                (KFmoc)WKY-NH.sub.2                                          3                (KFmoc)WKK-NH.sub.2                                          3                (KFmoc)WKT-NH.sub.2                                          3                (KFmoc)WKR-NH.sub.2                                          3                (KFmoc)WKG-NH.sub.2                                          3                (KFmoc)WKZ-NH.sub.2                                          3                (KFmoc)WKL-NH.sub.2                                          3                (KFmoc)WKH-NH.sub.2                                          3                (KFmoc)WKV-NH.sub.2                                          3                (KFmoc)WKI-NH.sub.2                                          3                (KFmoc)WKN-NH.sub.2                                          3                (KFmoc)WKA-NH.sub.2                                          3                (KFmoc)WKQ-NH.sub.2                                          3                (KFmoc)WKP-NH.sub.2                                          3                (KFmoc)WKD-NH.sub.2                                          3                (KFmoc)WKE-NH.sub.2                                          2                (KFmoc)WZZ-NH.sub.2                                          1                (KFmoc)ZZZ-NH.sub.2                                          --               (KFmoc)WKw-NH.sub.2                                          --               (KFmoc)WKc-NH.sub.2                                          --               (KFmoc)WKl-NH.sub.2                                          --               (KFmoc)WKs-NH.sub.2                                          --               (KFmoc)WKh-NH.sub.2                                          --               (KFmoc)WKy-NH.sub.2                                          --               (KFmoc)WKr-NH.sub.2                                          --               (KFmoc)WKa-NH.sub.2                                          --               (KFmoc)WKq-NH.sub.2                                          --               (KFmoc)WKm-NH.sub.2                                          --               (KFmoc)WKz-NH.sub.2                                          --               (KFmoc)WKp-NH.sub.2                                          --               (KFmoc)WKk-NH.sub.2                                          --               (KFmoc)WKi-NH.sub.2                                          --               (KFmoc)WKv-NH.sub.2                                          --               (KFmoc)WKt-NH.sub.2                                          --               (KFmoc)WKf-NH.sub.2                                          --               (KFmoc)WKn-NH.sub.2                                          --               (KFmoc)WKd-NH.sub.2                                          --               (KFmoc)WKe-NH.sub.2                                          3                (KFmoc)WK(NO.sub.2 F)-NH.sub.2                               3                (KFmoc)WK(Orn)-NH.sub.2                                      3                (KFmoc)WK(dOrn)-NH.sub.2                                     3                (KFmoc)WK(aABA)-NH.sub.2                                     3                (KFmoc)WK(Nle)-NH.sub.2                                      3                (KFmoc)WKZ-NH.sub.2                                          3                (KFmoc)WK(KFmoc)-NH.sub.2                                    3                (KFmoc)WK(aAIB)-NH.sub.2                                     3                (KFmoc)WK(KCBZ)-NH.sub.2                                     3                (KFmoc)WK(MetO.sub.2)-NH.sub.2                               3                (KFmoc)WK(Hyp)-NH.sub.2                                      3                (KFmoc)WK(Nve)-NH.sub.2                                      3                (KFmoc)WK(Cys ACM!)-NH.sub.2                                 3                (KFmoc)WK(Bala)-NH.sub.2                                     3                (KFmoc)WK(Thiopro)-NH.sub.2                                  3                (KFmoc)WK(bAsp)-NH.sub.2                                     3                (KFmoc)WK(7aHa)-NH.sub.2                                     3                (KFmoc)WK(gGlu)-NH.sub.2                                     3                (KFmoc)WK(gABA)-NH.sub.2                                     3                (KFmoc)WK(eAca)-NH.sub.2                                     4                (KFmoc)WYR-NH.sub.2                                          4                (KFmoc)WYK-NH.sub.2                                          4                (KFmoc)WYL-NH.sub.2                                          4                (KFmoc)WYW-NH.sub.2                                          4                (KFmoc)WYT-NH.sub.2                                          4                (KFmoc)WYH-NH.sub.2                                          4                (KFmoc)WYY-NH.sub.2                                          4                (KFmoc)WYZ-NH.sub.2                                          4                (KFmoc)WYP-NH.sub.2                                          4                (KFmoc)WYV-NH.sub.2                                          4                (KFmoc)WYG-NH.sub.2                                          4                (KFmoc)WYA-NH.sub.2                                          4                (KFmoc)WYN-NH.sub.2                                          4                (KFmoc)WYS-NH.sub.2                                          4                (KFmoc)WYQ-NH.sub.2                                          4                (KFmoc)WYM-NH.sub.2                                          4                (KFmoc)WYI-NH.sub.2                                          4                (KFmoc)WYC-NH.sub.2                                          4                (KFmoc)WYF-NH.sub.2                                          2                (KFmoc)WZZ-NH.sub.2                                          1                (KFmoc)ZZZ-NH.sub.2                                          --               (KFmoc)WYr-NH.sub.2                                          --               (KFmoc)WYs-NH.sub.2                                          --               (KFmoc)WYa-NH.sub.2                                          --               (KFmoc)WYk-NH.sub.2                                          --               (KFmoc)WYp-NH.sub.2                                          --               (KFmoc)WYn-NH.sub.2                                          --               (KFmoc)WYh-NH.sub.2                                          --               (KFmoc)WYl-NH.sub.2                                          4                (KFmoc)WYZ-NH.sub.2                                          --               (KFmoc)WYm-NH.sub.2                                          --               (KFmoc)WYv-NH.sub.2                                          --               (KFmoc)WYt-NH.sub.2                                          --               (KFmoc)WYq-NH.sub.2                                          --               (KFmoc)WYi-NH.sub.2                                          --               (KFmoc)WYf-NH.sub.2                                          --               (KFmoc)WYw-NH.sub.2                                          --               (KFmoc)WYc-NH.sub.2                                          --               (KFmoc)WYy-NH.sub.2                                          4                (KFmoc)WY(aABA)-NH.sub.2                                     4                (KFmoc)WY(7aHa)-NH.sub.2                                     4                (KFmoc)WY(dOrn)-NH.sub.2                                     4                (KFmoc)WY(Orn)-NH.sub.2                                      4                (KFmoc)WYZ-NH.sub.2                                          4                (KFmoc)WY(KCBZ)-NH.sub.2                                     4                (KFmoc)WY(Hyp)-NH.sub.2                                      4                (KFmoc)WY(aAIB)-NH.sub.2                                     4                (KFmoc)WY(Nle)-NH.sub.2                                      4                (KFmoc)WY(eAca)-NH.sub.2                                     4                (KFmoc)WY(NO.sub.2 F)-NH.sub.2                               4                (KFmoc)WY(Bala)-NH.sub.2                                     4                (KFmoc)WY(Thiopro)-NH.sub.2                                  4                (KFmoc)WY(Nve)-NH.sub.2                                      4                (KFmoc)WY(Cys ACM!)-NH.sub.2                                 4                (KFmOC)WY(gABA)-NH.sub.2                                     4                (KFmoc)WY(MetO.sub.2)-NH.sub.2                               --               (KFmoc)WfR-NH.sub.2                                          --               (KFmoc)WfL-NH.sub.2                                          --               (KFmoc)WfP-NH.sub.2                                          --               (KFmoc)WfZ-NH.sub.2                                          --               (KFmoc)WfK-NH.sub.2                                          --               (KFmoc)WfN-NH.sub.2                                          --               (KFmoc)WfH-NH.sub.2                                          --               (KFmoc)WfT-NH.sub.2                                          --               (KFmoc)WfV-NH.sub.2                                          --               (KFmoc)WfS-NH.sub.2                                          --               (KFmoc)WfA-NH.sub.2                                          --               (KFmoc)WfM-NH.sub.2                                          --               (KFmoc)WfF-NH.sub.2                                          --               (KFmoc)WfC-NH.sub.2                                          --               (KFmoc)WfI-NH.sub.2                                          --               (KFmoc)WfY-NH.sub.2                                          2                (KFmoc)WZZ-NH.sub.2                                          1                (KFmoc)ZZZ-NH.sub.2                                          --               (KFmoc)Wfl-NH.sub.2                                          --               (KFmoc)Wfw-NH.sub.2                                          --               (KFmoc)Wfr-NH.sub.2                                          --               (KFmoc)Wfi-NH.sub.2                                          --               (KFmoc)WfZ-NH.sub.2                                          --               (KFmoc)Wff-NH.sub.2                                          --               (KFmoc)Wfm-NH.sub.2                                          --               (KFmoc)Wfv-NH.sub.2                                          --               (KFmoc)Wfp-NH.sub.2                                          --               (KFmoc)Wft-NH.sub.2                                          --               (KFmoc)Wfa-NH.sub.2                                          --               (KFmoc)Wfs-NH.sub.2                                          --               (KFmoc)Wfh-NH.sub.2                                          --               (KFmoc)Wfk-NH.sub.2                                          --               (KFmoc)Wfq-NH.sub.2                                          --               (KFmoc)Wfy-NH.sub.2                                          --               (KFmoc)Wfc-NH.sub.2                                          --               (KFmoc)Wfn-NH.sub.2                                          --               (KFmoc)Wf(KCBZ)-NH.sub.2                                     --               (KFmoc)Wf(Thiopro)-NH.sub.2                                  --               (KFmoc)Wf(dOrn)-NH.sub.2                                     --               (KFmoc)Wf(Orn)-NH.sub.2                                      --               (KFmoc)Wf(aAIB)-NH.sub.2                                     --               (KFmoc)WfZ-NH.sub.2                                          --               (KFmoc)Wf(MetO.sub.2)-NH.sub.2                               --               (KFmoc)Wf(Hyp)-NH.sub.2                                      --               (KFmoc)Wf(Nve)-NH.sub.2                                      --               (KFmoc)Wf(aABA)-NH.sub.2                                     --               (KFmoc)Wf(7aHa)-NH.sub.2                                     --               (KFmoc)Wf(Nle)-NH.sub.2                                      --               (KFmoc)Wf(NO.sub.2 F)-NH.sub.2                               --               (KFmoc)Wf(gABA)-NH.sub.2                                     --               (KFmoc)Wf(Bala)-NH.sub.2                                     --               (KFmoc)Wf(Cys ACM!)-NH.sub.2                                 --               (KFmoc)ciR-NH.sub.2                                          --               (KFmoc)ciK-NH.sub.2                                          --               (KFmoc)ciP-NH.sub.2                                          --               (KFmoc)ciM-NH.sub.2                                          --               (KFmoc)ciH-NH.sub.2                                          --               (KFmoc)ciA-NH.sub.2                                          --               (KFmoc)ciW-NH.sub.2                                          --               (KFmoc)ciT-NH.sub.2                                          --               (KFmoc)ciL-NH.sub.2                                          --               (KFmoc)ciZ-NH.sub.2                                          --               (KFmoc)ciY-NH.sub.2                                          --               (KFmoc)ciS-NH.sub.2                                          --               (KFmoc)ciI-NH.sub.2                                          --               (KFmoc)ciF-NH.sub.2                                          --               (KFmoc)ciN-NH.sub.2                                          --               (KFmoc)ciV-NH.sub.2                                          --               (KFmoc)cZZ-NH.sub.2                                          1                (KFmoc)ZZZ-NH.sub.2                                          --               (KFmoc)cir-NH.sub.2                                          --               (KFmoc)cik-NH.sub.2                                          --               (KFmoc)cip-NH.sub.2                                          --               (KFmoc)cil-NH.sub.2                                          --               (KFmoc)ciZ-NH.sub.2                                          --               (KFmoc)cit-NH.sub.2                                          --               (KFmoc)ciw-NH.sub.2                                          --               (KFmoc)cim-NH.sub.2                                          --               (KFmoc)cic-NH.sub.2                                          --               (KFmoc)cif-NH.sub.2                                          --               (KFmoc)ciy-NH.sub.2                                          --               (KFmoc)cis-NH.sub.2                                          --               (KFmoc)ci(aAIB)-NH.sub.2                                     --               (KFmoc)ci(Orn)-NH.sub.2                                      --               (KFmoc)ci(dOrn)-NH.sub.2                                     --               (KFmoc)ci(KCBZ)-NH.sub.2                                     --               (KFmoc)ci(aABA)-NH.sub.2                                     --               (KFmoc)ci(Hyp)-NH.sub.2                                      --               (KFmoc)ci(Thiopro)-NH.sub.2                                  --               (KFmoc)ciZ-NH.sub.2                                          --               (KFmoc)ci(KFmoc)-NH.sub.2                                    --               (KFmoc)ci(7aHa)-NH.sub.2                                     --               (KFmoc)ci(eAca)-NH.sub.2                                     --               (KFmoc)ci(Nve)-NH.sub.2                                      --               (KFmoc)ci(Nle)-NH.sub.2                                      --               (KFmoc)ci(NO.sub.2 F)-NH.sub.2                               ______________________________________                                    

In particular, this invention provides anti-microbial peptides havingthe formula (KFmoc)ZZZ-NH₂ SEQ ID NO: 1!, wherein Z is an amico acidsaid peptide having an IC₅₀ less than 30 μgms/ml and more particularly,HD₅₀ (% hemolysis) greater than 100 μgms/ml.

This invention provides compositions comprising anti-microbial orhemolytic peptides, in particular having the formula (KFmoc)ZZZ-NH₂ SEQID NO: 1!, wherein Z is an amino acid, in an acceptable carrier. Thesecompositions find use as disinfectants and in methods to retard thegrowth of microorganisms. They also find use in methods of treatingsubjects with microbial infections. Compositions comprising hemolyticpeptides find use, e.g., in diagnostic procedures requiring lysis of redblood cells.

This invention provides pharmaceutical compositions comprising a peptidehaving the formula (KFmoc)ZZZ-NH₂, wherein Z is an amino acid in apharmaceutically acceptable carrier, said peptide having anti-microbialactivity. In particular, this invention provides pharmaceuticalcompositions in which the peptide has HD₅₀ greater than 100 μgms/ml.

This invention provides methods of treating a subject infected with amicroorganism comprising the step of administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a peptide having the formula (KFmoc)ZZZ-NH₂ SEQ ID NO: 1!,wherein Z is an amino acid, said peptide having anti-microbial activityagainst the said microorganism. In particular, this invention providesmethods in which the peptide has HD₅₀ greater than 100 μgms/ml.

This invention provides methods of inhibiting the growth of amicroorganism comprising the step of contacting the microorganism withan effective amount of a peptide having the formula (KFmoc)ZZZ-NH₂ SEQID NO: 1!, wherein Z is an amino acid, said peptide havinganti-microbial activity against the microorganism. In particular, thisinvention provides this method wherein the peptide has HD₅₀ greater than100 μgms/ml. An effective amount is at least the IC₅₀ concentration.

This invention also provides methods of lysing red blood cellscomprising the step of contacting red blood cells with an effectiveamount of a peptide having the formula (KFmoc)ZZZ-NH₂ SEQ ID NO: 1!,wherein Z is an amino acid, and the peptide has HD₅₀ less then 100μgms/ml. An effective amount is at least the IC₅₀ concentration.

B. Ac-RRWWCZ-NH₂ SEQ ID NO: 6!

This invention provides methods using anti-microbial peptides having thegeneral formulae:

    ______________________________________                                        SEQUENCE ID NO:    PEPTIDE                                                    ______________________________________                                        5                  Ac-RRWWZZ-NH.sub.2                                         6                  Ac-RRWWCZ-NH.sub.2,                                        ______________________________________                                    

wherein Z is an amino acid.

In particular, this invention provides methods using peptides having theformula:

    ______________________________________                                        SEQUENCE ID NO:    PEPTIDE                                                    ______________________________________                                        6                  Ac-RRWWCA-NH.sub.2                                         6                  Ac-RRWWCC-NH.sub.2                                         6                  Ac-RRWWCD-NH.sub.2                                         6                  Ac-RRWWCE-NH.sub.2                                         6                  Ac-RRWWCF-NH.sub.2                                         6                  Ac-RRWWCG-NH.sub.2                                         6                  Ac-RRWWCH-NH.sub.2                                         6                  Ac-RRWWCI-NH.sub.2                                         6                  Ac-RRWWCK-NH.sub.2                                         6                  Ac-RRWWCL-NH.sub.2                                         6                  Ac-RRWWCM-NH.sub.2                                         6                  Ac-RRWWCN-NH.sub.2                                         6                  Ac-RRWWCP-NH.sub.2                                         6                  Ac-RRWWCQ-NH.sub.2                                         6                  Ac-RRWWCR-NH.sub.2                                         6                  Ac-RRWWCS-NH.sub.2                                         6                  Ac-RRWWCT-NH.sub.2                                         6                  Ac-RRWWCV-NH.sub.2                                         6                  Ac-RRWWCW-NH.sub.2                                         6                  Ac-RRWWCY-NH.sub.2                                         ______________________________________                                    

This invention also provides pharmaceutical compositions comprising apeptide having the formula Ac-RRWWCZ-NH₂ SEQ ID NO: 6!, wherein Z is anamino acid, in a pharmaceutically acceptable carrier, said peptidehaving an IC₅₀ less than 30 μgms/ml against E. coli, S. aureus, S.sangiunis, C. albicans or P. aeruginosa. In particular, this inventionprovides pharmaceutical compositions in which the peptide has HD₅₀greater than 100 μgms/ml.

This invention also provides methods of treating a subject infected witha gram-negative bacterium (e.g. E. coli or P. aeruginosa), or a yeast(e.g. C. albicans) comprising the step of administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a peptide having the formula Ac-RRWWCZ-NH₂ SEQ ID NO: 6!, orAc-rrwwcz-NH₂ SEQ ID NO: 6!, wherein z is a D-amino acid, in apharmaceutically acceptable carrier, said peptide having an IC₅₀ lessthan 30 μgms/ml against the microorganism. In particular, this inventionprovides methods in which the peptide has HD₅₀ greater than 100 μgms/ml.

This invention also provides methods of inhibiting the growth of agram-negative bacterium (e.g. E. coli or P. aeruginosa), or a yeast(e.g., C. albicans) comprising the step of contacting the microorganismwith an effective amount of a peptide having the formula Ac-RRWWCZ-NH₂,wherein Z is an amino acid, said peptide having an IC₅₀ less than 30μgms/ml against the microorganism. In particular, this invention providemethods wherein the peptide has HD₅₀ greater than 100 μgms/ml. Aneffective amount is at least the IC₅₀ concentration.

This invention also provides methods of lysing red blood cellscomprising the step of contacting red blood cells with an effectiveamount of a peptide having the formula Ac-RRWWCZ-NH₂, wherein Z is anamino acid, wherein the peptide has HD₅₀ less than 100 μgms/ml. Aneffective amount is at least the IC₅₀ concentration.

C. Ac-rrwwz-NH₂

This invention also provides anti-microbial peptides having the formula:

    ______________________________________                                        SEQUENCE ID NO:      PEPTIDE                                                  ______________________________________                                        --                   Ac-rrwwz-NH.sub.2,                                       ______________________________________                                    

wherein Z is an amino acid, and, in particular, wherein z is a D-aminoacid; wherein the peptide has anti-microbial activity IC₅₀ less than 30μgms/ml and more particularly, less than 10 μgms/ml. It also providesthese peptides having HD₅₀ greater than 100 μgms/ml.

In particular, this invention provides peptides having the formula:

    ______________________________________                                        SEQUENCE ID NO:      PEPTIDE                                                  ______________________________________                                        --                   Ac-rrwwcr-NH.sub.2                                       --                   Ac-rrwwcv-NH.sub.2                                       ______________________________________                                    

This invention provides pharmaceutical compositions comprising a peptidehaving the formula (KFmoc)ZZZ-NH₂, wherein Z is an amino acid in apharmaceutically acceptable carrier, said peptide having anti-microbialactivity. In particular, this invention provides pharmaceuticalcompositions in which the peptide has HD₅₀ greater than 100 μgms/ml.

This invention provides methods of treating a subject infected with amicroorganism comprising the step of administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a peptide having the formula wherein z is a D-amino acid saidpeptide having anti-microbial activity against the said microorganism.In particular, this invention provides methods in which the peptide hasHD₅₀ greater than 100 μgms/ml.

This invention provides methods of inhibiting the growth of amicroorganism comprising the step of contacting the microorganism withan effective amount of a peptide having the formula wherein z is aD-amino acid said peptide having anti-microbial activity against themicroorganism. In particular, this invention provides this methodwherein the peptide has HD₅₀ greater than 100 μgms/ml. An effectiveamount is at least the IC₅₀ concentration.

This invention also provides methods of lysing red blood cellscomprising the step of contacting red blood cells with an effectiveamount of a peptide having the formula wherein z is a D-amino acid andthe peptide has HD₅₀ less than 100 μgms/ml. An effective amount is atleast the IC₅₀ concentration.

II. ANTI-MELITTIN PEPTIDES

This invention provides peptides having anti-melittin activity. Melittinis the active compound in bee venom, and causes cell lysis. It has theformula:

    ______________________________________                                        SEQ ID NO: PEPTIDE                                                            ______________________________________                                        7          GIGAVLKVLT TGLPALISW IKRKRQQ-NH.sub.2                              ______________________________________                                    

One can synthesize melittin by any known method for peptide synthesis.

This invention provides peptides having anti-melittin activity havingthe general formulae:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                         8                 Ac-IVILZZ-NH.sub.2                                          9                 Ac-IVILTZ-NH.sub.2                                         10                 Ac-IVILLZ-NH.sub.2                                         11                 Ac-IVIFFZ-NH.sub.2                                         ______________________________________                                    

wherein Z is an amino acid.

In particular, this invention provides peptides having the formula:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                         9                 Ac-IVILTM-NH.sub.2                                          9                 Ac-IVILTF-NH.sub.2                                          9                 Ac-IVILTL-NH.sub.2                                          9                 Ac-IVILTQ-NH.sub.2                                          9                 Ac-IVILTW-NH.sub.2                                          9                 Ac-IVILTA-NH.sub.2                                          9                 Ac-IVILTN-NH.sub.2                                          9                 Ac-IVILTY-NH.sub.2                                          9                 Ac-IVILTC-NH.sub.2                                          9                 Ac-IVILTV-NH.sub.2                                          9                 Ac-IVILTG-NH.sub.2                                          9                 Ac-IVILTE-NH.sub.2                                          9                 Ac-IVILTS-NH.sub.2                                          9                 Ac-IVILTT-NH.sub.2                                          9                 Ac-IVILTP-NH.sub.2                                          9                 Ac-IVILTH-NH.sub.2                                          9                 Ac-IVILTI-NH.sub.2                                          9                 Ac-IVILTK-NH.sub.2                                          9                 Ac-IVILTR-NH.sub.2                                         10                 Ac-IVILLW-NH.sub.2                                         10                 Ac-IVILLE-NH.sub.2                                         10                 Ac-IVILLQ-NH.sub.2                                         10                 Ac-IVILLY-NH.sub.2                                         10                 Ac-IVILLN-NH.sub.2                                         10                 Ac-IVILLS-NH.sub.2                                         10                 Ac-IVILLA-NH.sub.2                                         10                 Ac-IVILLG-NH.sub.2                                         10                 Ac-IVILLD-NH.sub.2                                         10                 Ac-IVILLT-NH.sub.2                                         10                 Ac-IVILLM-NH.sub.2                                         10                 Ac-IVILLF-NH.sub.2                                         10                 Ac-IVILLP-NH.sub.2                                         10                 Ac-IVILLI-NH.sub.2                                         10                 Ac-IVILLV-NH.sub.2                                         10                 Ac-IVILLL-NH.sub.2                                         10                 Ac-IVILLC-NH.sub.2                                         10                 Ac-IVILLH-NH.sub.2                                         10                 Ac-IVILLK-NH.sub.2                                         10                 Ac-IVILLR-NH.sub.2                                         11                 Ac-IVIFFD-NH.sub.2                                         11                 Ac-IVIFFE-NH.sub.2                                         11                 Ac-IVIFFW-NH.sub.2                                         11                 Ac-IVIFFN-NH.sub.2                                         11                 Ac-IVIFFM-NH.sub.2                                         11                 Ac-IVIFFY-NH.sub.2                                         11                 Ac-IVIFFS-NH.sub.2                                         11                 Ac-IVIFFG-NH.sub.2                                         11                 Ac-IVIFFT-NH.sub.2                                         11                 Ac-IVIFFA-NH.sub.2                                         11                 Ac-IVIFFQ-NH.sub.2                                         11                 Ac-IVIFFV-NH.sub.2                                         11                 Ac-IVIFFH-NH.sub.2                                         11                 Ac-IVIFFP-NH.sub.2                                         11                 Ac-IVIFFC-NH.sub.2                                         11                 Ac-IVIFFI-NH.sub.2                                         11                 Ac-IVIFFL-NH.sub.2                                         11                 Ac-IVIFFF-NH.sub.2                                         11                 Ac-IVIFFK-NH.sub.2                                         11                 Ac-IVIFFR-NH.sub.2                                         ______________________________________                                    

This invention provides peptides having anti-melittin activity havingthe formula:

    ______________________________________                                        SEQ ID NO:       PEPTIDE                                                      ______________________________________                                        12               Ac-Z.sub.1 Z.sub.2 IZ.sub.3 Z.sub.4 Z.sub.5 -NH.sub.2,       ______________________________________                                    

wherein Z₁, Z₂, Z₃, Z₄ and Z₅ are amino acids, and in particular whereinZ₁ is F or I; Z₂ is I, Q or D; Z₃ is W or Y; Z₄ is C or F and Z₅ is E orK.

In particular, this invention is directed to peptides having theformula:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                        12                 Ac-FIIWCE-NH.sub.2                                         12                 Ac-IIIWCE-NH.sub.2                                         12                 Ac-FIIYCE-NH.sub.2                                         12                 AC-IQIYCE-NH.sub.2                                         12                 Ac-IIIYFE-NH.sub.2                                         12                 Ac-IIIWFE-NH.sub.2                                         12                 Ac-FIIWFE-NH.sub.2                                         12                 Ac-IQIWCE-NH.sub.2                                         12                 Ac-FIIYFE-NH.sub.2                                         12                 Ac-FQIWFE-NH.sub.2                                         12                 Ac-FQIWCE-NH.sub.2                                         12                 Ac-IIIYCE-NH.sub.2                                         12                 Ac-FQIYCE-NH.sub.2                                         12                 Ac-IQIYFE-NH.sub.2                                         12                 Ac-FQIYFE-NH.sub.2                                         12                 Ac-IQIWFE-NH.sub.2                                         12                 Ac-IDIWCK-NH.sub.2                                         12                 Ac-FDIWFK-NH.sub.2                                         12                 Ac-FDIWFE-NH.sub.2                                         12                 Ac-FDIYCE-NH.sub.2                                         12                 Ac-IDIYCE-NH.sub.2                                         12                 Ac-IDIYFE-NH.sub.2                                         12                 Ac-FIIYFK-NH.sub.2                                         12                 Ac-IDIYFK-NH.sub.2                                         12                 Ac-IDIWCE-NH.sub.2                                         12                 Ac-FDIYFE-NH.sub.2                                         12                 Ac-IQIYCK-NH.sub.2                                         12                 Ac-FIIWFK-NH.sub.2                                         ______________________________________                                    

This invention also provides peptides having the formula:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                        13                 Ac-MILWIE-NH.sub.2                                         14                 Ac-VIQQFV-NH.sub.2                                         15                 AC-WIQIFI-NH.sub.2                                         ______________________________________                                    

In particular, this invention also provides anti-melittin peptideshaving IC₅₀ less than 30 μgms/ml.

This invention provides methods of inhibiting melittin activitycomprising the step of contacting melittin with an effective amount of apeptide having the formula Ac-IVILTZ-NH₂ SEQ ID NO: 9!, Ac-IVILLZ-NH₂SEQ ID NO: 10!, Ac-IVIFFZ-NH₂ SEQ ID NO: 11!, having an IC₅₀ less than30 μgms/ml. An effective amount is at least the IC₅₀ concentration.

This invention also provides compositions comprising a peptide havingthe formula Ac-IVILTZ-NH₂ SEQ ID NO: 9!, Ac-IVILLZ-NH₂ SEQ ID NO: 10!,Ac-IVIFFZ-NH₂ SEQ ID NO: 11!, or Ac-Z₁ Z₂ IZ₃ Z₄ Z₅ -NH₂, wherein Z isan amino acid, Ac-MILWIE-NH₂, Ac-VIQQFV-NH₂, Ac-WIQIFI-NH₂ in anacceptable carrier.

This invention also provides pharmaceutical compositions comprising apeptide having the formula Ac-IVILTZ-NH₂ SEQ ID NO: 6!, Ac-IVILLZ-NH₂SEQ ID NO: 10!, Ac-IVIFFZ-NH₂ SEQ ID NO: 11!, or Ac-Z₁ Z₂ IZ₃ Z₄ Z₅ -NH₂SEQ ID NO: 12!, wherein Z is an L-amino acid, Ac-MILWIE-NH₂,Ac-VIQQFV-NH₂, Ac-WIQIFI-NH₂ in a pharmaceutically acceptable carrier.

This invention also provides methods of treating a subject sufferingfrom melittin poisoning comprising the step of administering to thesubject a therapeutically effective amount of a pharmaceuticalcomposition comprising a peptide of having the formula Ac-IVILTZ-NH₂ SEQID NO: 9!, Ac-IVILLZ-NH₂ SEQ ID NO: 10!, Ac-IVIFFZ-NH₂ SEQ ID NO: 11!,or Ac-Z₁ Z₂ IZ₃ Z₄ Z₅ SEQ ID NO: 12!, wherein Z is an L-amino acid, saidpeptide having an HD₅₀ greater than 100 μgms/ml. Melittin poisoningresults from introducion of melittin into a subject to cause significantcell lysis, for example by bee sting.

III. ANTI-TRYPSIN PEPTIDES

This invention provides all-D-amino acid anti-trypsin peptides having anIC₅₀ less than 150 μM at a trypsin concentration of 193 nM. Thesepeptides find use in methods of inhibiting trypsin activity. Forexample, these peptides find use in quenching trypsin activity in assaysor procedures calling for limited trypsin digestion.

In particular, this invention provides peptides having the formula:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                        --                 Ac-ryrpwz-NH.sub.2                                         ______________________________________                                    

wherein z is a D-amino acid.

More particularly, this invention provides the peptides:

    ______________________________________                                        SEQ ID NO:         PEPTIDE                                                    ______________________________________                                        --                 Ac-ryrpwp-NH.sub.2                                         --                 Ac-ryrpww-NH.sub.2                                         --                 Ac-ryrpwv-NH.sub.2                                         --                 Ac-ryrpwc-NH.sub.2                                         --                 Ac-ryrpwt-NH.sub.2                                         ______________________________________                                    

This invention also provides methods of inhibiting trypsin activitycomprising the step of contacting trypsin with an effective amount of apeptide having the formula Ac-ryrpwz-NH₂, wherin z is a D-amino acid. Aneffective amount is at least the IC₅₀ concentration.

One skilled in the art can easily produce any of the individual peptidesof this invention by simultaneous multi peptide synthesis (Example I) orby synthesis on an automated peptide synthesizer, according to themanufacturer's instructions (Model 430A, Applied Biosystems, FosterCity, Calif. USA).

This invention provides pharmaceutical compositions comprising thepeptides of this invention in a pharmaceutically acceptable carrier. Asused herein, the term "pharmaceutically acceptable carrier" encompassesany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, and emulsions, such as an oil/water orwater/oil emulsion, and various types of wetting agents.

Suitable pharmaceutical carriers and their formulations are described inMartin, REMINGTON'S PHARMACEUTICAL SCIENCES, 15th Ed. (Mack PublishingCo., Easton 1975). Such compositions will, in general, contain aneffective amount of the active reagent together with a suitable amountof carrier so as to prepare the proper dosage form for properadministration to the subject.

Useful pharmaceutical carriers for the preparation of the pharmaceuticalcompositions can be solids, liquids or gases. Thus, the compositions cantake the form of tablets, pills, capsules, powders, enterically coatedor other protected formulations (such as by binding on ion exchangeresins or other carriers, or packaging in lipid protein vesicles oradding additional terminal amino acids), sustained release formulations,solutions (e.g. ophthalmic drops), suspensions, elixirs, aerosols, andthe like. Water, saline, aqueous dextrose, and glycols are preferredliquid carriers, particularly (when isotonic) for injectable solutions.The carrier can be selected from various oils including those ofpetroleum, animal, vegetable or synthetic origin, for example, peanutoil, soybean oil, mineral oil, sesame oil, and the like. Suitablepharmaceutical excipients include starch, cellulose. talc, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel,magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, glycerol, propylene glycol, water, ethanol,and the like.

The compositions may be subjected to conventional pharmaceuticalprocedures such as sterilization and may contain conventionalpharmaceutical additives such as preservatives, stabilizing agents,wetting or emulsifying agents, salts for adjusting osmotic pressure,buffers, and the like.

This invention provides methods of treating a subject comprising thestep of administering a therapeutically effective amount of apharmaceutical composition of this invention to a subject. As usedherein, the term "therapeutically effective amount" is that amountnecessary to alleviate the condition from which the subject suffers. Asused herein, the term "subject" includes animals, vertebrates, mammalsor humans.

In the practice of the therapeutic methods of the present invention, aneffective amount of a peptide of this invention, including derivativesor salts thereof, or a pharmaceutical composition containing the same,as described above, is administered via any of the usual and acceptablemethods known in the art, either singly or in combination with anotherpeptide or peptides of the present invention or other pharmaceuticalagents such as anti-inflammatory agents, or other therapeutics known tohave an effect on inflammation or the like. These compounds orcompositions can thus be administered orally, sublingually, topically(e.g., on the skin or in the eyes), parenterally (e.g., intramuscularly,intravenously, subcutaneously or intradermally), or by inhalation, andin the form of either solid, liquid or gaseous dosage including tablets,suspensions, and aerosols, as is discussed in more detail above. Theadministration can be conducted in single unit dosage form withcontinuous therapy or in single dose therapy ad libitum.

In one embodiment, the therapeutic methods of the present invention arepracticed when the relief of symptoms is specifically required orperhaps imminently so. In another embodiment, the method is effectivelypracticed as continuous or prophylactic treatment.

In the practice of the therapeutic methods of the invention, theparticular dosage of pharmaceutical composition to be administered tothe subject will depend on a variety of considerations including thenature of the disease, the severity thereof, the schedule ofadministration, the age and physical characteristics of the subject, andso forth. Proper dosages may be established using clinical approachesfamiliar to the medicinal arts. It is presently believed that dosages inthe range 0.1 of 100 mg of a peptide of this invention per kilogram ofsubject body weight will be useful, and a range of 1 to 100 mg per kggenerally preferred where the administration is by injection oringestion. Topical dosages may utilize formulations containing activepeptides and a liquid carrier or excipient, with multiple dailyapplications being appropriate.

This invention also provides methods of inhibiting the growth ofmicroorganisms comprising the step of contacting the microorganism withan effective amount of a peptide of this invention. Methods ofcontacting a microorganism with a peptide of this invention include, forexample, those described in Example I, Section B.

This invention provides methods of inhibiting melittin activitycomprising the step of contacting melittin with an effective amount of apeptide of this invention. Such methods include, for example, thosedescribed in Example II, Section B.

This invention provides methods of inhibiting trypsin activitycomprising the step of contacting trypsin with an effective amount of apeptide of this invention. Such methods include, for example, thosedescribed in Example III, Section B.

EXAMPLE I PEPTIDES HAVING ANTI-MICROBIAL ACTIVITY

A. Synthetic Peptide Libraries

A synthetic peptide library was prepared using methylbenzhydrylamine(MBHA) polystyrene resin and standard t-Boc chemistry in combinationwith simultaneous multiple peptide synthesis (SMPS) (R. A. Houghten,Proc. Natl. Acad. Sci. U.S.A. 82., 5131-5135 (1985); U.S. Pat. No.4,631,211 (each of which is incorporated herein by reference)). Adivide, couple and recombine (DCR) process was used to synthesize theXXXX-peptide resin wherein X is an eguimolarmixture of selected aminoacids. This process assures equimolarity of the peptides on the resin.

Briefly, 18 porous polypropylene packets, each containing 4.65 mmol(5.00 g) of MBHA resin, were coupled to each of the protected N-α-t-Bocamino acids of interest. All coupling reactions proceeded to completion(greater than 99.5%), as assessed by Gisin's picric acid (B. F. Gisin,Analytica Chim. Acta. 58, 248-249 (1972)) or Kaiser's ninhydrin tests(E. T. Kaiser, Analyt. Biochem 34, 595-598 (1970)).

The resulting resins from each packet were then combined and thoroughlymixed. This resin mixture was separated into 18 portions of equal weightwhich were placed into porous polypropylene packets, followed byN-α-t-Boc protecting group removal and neutralization of the resultingamine TFA salts. The resin packets were then reacted with solutions ofthe individual activated amino acids to yield the 324 dipeptidecombinations (18²).

The above DCR process was repeated twice more, yielding a final mixtureof 104,976 protected tetra-peptide resins (18⁴). This XXXX-resin wasdivided into 324 aliquots (150 mg each) and placed in numbered, porouspolypropylene packets.

Synthesis of the next two defined positions was carried out by SMPS. Thepeptide mixtures were deprotected and cleaved from their respectiveresins using low-high hydrogen fluoride (HF) (J. P. Tam et al., J. Am.Chem. Soc. 105, 6442-6455 (1983)) as described for individual peptidesearlier (J. H. Cuervo et al., Peptide Res. 1, 81-86 (1988); and R. A.Boughten et al., Int. J. Peptide Protein Res. 27, 673-678 (1986)) in amultiple HF cleavage apparatus (Multiple Peptide Systems, San Diego,Calif.). Extraction of the individual peptide mixtures was carried outwith distilled water.

B. Antimicrobial Assays

1. E. coli, P. aeruginosa and S. aureus

Escherichia coli ATCC 25922 and P. aeruginosa ATCC 27853 were used asGram-negative (-) and Staphylococcus aureus ATCC 29213 as Gram-positive(+) bacteria. Bacteria were grown overnight at 37° C. in Mueller-Hinton(MH) broth. This culture was reinoculated and incubated at 37° C. toreach the exponential phase of bacteria growth, i.e., a final bacterialsuspension containing 10⁵ to 5×10⁵ colony-forming units (CFU)/ml. Theconcentration of cells was established by plating 100 μl of differentdilutions of the culture solution (e.g., 10⁻², 10⁻² and 10⁻⁴) onto solidagar plates.

Following an overnight incubation at 37° C., the CFU thus formed werecounted on each agar plate. In 96-well tissue culture plates, as controlblanks, eight wells per plate contained only medium, while as a positivegrowth control, eight other wells contained medium plus cells. Thesecontrols were used to detect possible medium contamination and toprovide a measure of uninhibited growth of the microorganisms.

For IC₅₀ (concentration necessary to inhibit 50% growth of bacteria),peptides were added to the bacterial suspension at concentrationsderived from two-fold dilutions ranging from 1000 μg/ml to 1.95 μg/ml.

The plates were incubated overnight at 37° C., and the optical density(OD) determined at 620 nm after different times of incubation.

2. S. sanguis

Streptococcus sanguis ATCC 10556 (Gram-positive (+) bacteria present intooth crevices) was grown overnight at 37° C. in Brain Heart Infusion(BHI) broth. This culture was reinoculated and incubated at 37° C. toreach the exponential phase of bacteria growth, i.e., a final bacterialsuspension containing 10⁵ to 5×10⁵ colony-forming units (CFU)/ml. Theconcentration of cells was established by plating 100 μl of differentdilutions of the culture solution (e.g., 10⁻², 10⁻³ and 10⁻⁴) onto solidagar plates. Following an overnight incubation at 37° C., the CFU thusformed were counted on each agar plate. In 96-well tissue cultureplates, as control blanks, eight wells per plate contained only medium,while as a positive growth control, eight other wells contained mediumplus cells. These controls were used to detect possible mediumcontamination and to provide a measure of uninhibited growth of themicroorganisms. For IC₅₀ (concentration necessary to inhibit 50% growthof bacteria), peptides are added to the bacterial suspension atconcentrations derived from two-fold dilutions ranging from 1000 μg/mlto 1.95 μg/ml. The plates were incubated overnight at 37° C., and theoptical density (OD) determined at 620 nm after 20 to 24 hoursincubation.

3. C. albicans

The organism used for antifungal studies was Candida albicans ATCC10231. The yeast culture was spread onto YM agar plates and incubated at30° C. for 48 hours. Three colonies of this culture (approx. 1 mm indiameter each) were then inoculated in 5 ml of 1X PBS solution. Thesuspension was vortexed and diluted 10-fold in YM broth, for anapproximate final concentration of 10⁵ to 5×10⁵ CFU (colony formingunits)/ml. Actual concentration of yeast culture was determined byplating 100 μl of different solutions of the culture solution (10⁻³,10⁻⁴, 10⁻⁵) onto solid YM agar plates.

After 48 hours of incubation at 30° C., CFU formed were counted fromeach plate. The assays were carried out in 96-well tissue cultureplates. Eight wells containing only medium of YM broth served asnegative controls while eight wells containing medium and yeast cultureserved as positive controls. These controls were used to detect possiblemedium contamination and to provide a measure of uninhibited growth ofthe yeast. The two antifungal drugs Amphotericin B and Nystatin (bothfrom Sigma Chemical, St. Louis, Mo., U.S.A.) were included in each assayfor comparative purpose.

For IC₅₀ (concentration necessary to inhibit 50% growth of the yeast)peptides were added to the yeast suspension at concentrations derivedfrom two-fold dilutions ranging from 1500 μg/ml to 3.13 μg/ml. Theplates were incubated over a period of 48 hours at 30° C., and theoptical density (OD) at 24 and 48 hours was determined at 620 nm.

C. Hemolytic Activity

Each assay was carried out in 96-well culture tissue plates. Four wellsper plate contain 125 μl of a non-peptide positive control (1% Triton inde-ionized water), and four wells per plate contain 125 μl of a controlblank, phosphate buffered saline (PBS). The hemolytic peptide melittinwas used as comparative control. The controls served to detect possiblecontamination and to calculate the percent hemolysis of each peptide.Human red blood cells (RBCs) were washed with PBS and centrifuged toseparate them from the serum. The cells were then resuspended in PBS toa final suspension of 0.5% RBC. 125 μl of this suspension was added tothe peptides and controls solution. The release of hemoglobin resultingfrom the cell lysis was determined by measuring the OD at 414 nm of 100μl of the supernatant.

The hemolytic doses, i.e., the concentration necessary to lyse 50% ofthe cells (HD₅₀), were determined by performing a serial two-folddilution of the peptide mixture solutions ranging from 1500 μg/ml to3.13 μg/ml.

D. Results

Tables 2-23 present data on the anti-microbial and hemolytic activitiesof various peptides. In Tables 2-21 "X" represents and equimolar mixtureof the amino acids of Table I, excluding D- and L- cysteine and D- andL- tryptophan.

                  TABLE 2                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST E. COLI OF                                     (KFmoc)WKZ-NH.sub.2                                                                         IC.sub.50          IC.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WKW-NH.sub.2                                                                           14      (KFmoc)WKw-NH.sub.2                                                                        15                                       (KFmoc)WKL-NH.sub.2                                                                           18      (KFmoc)WKl-NH.sub.2                                                                        20                                       (KFmoc)WKF-NH.sub.2                                                                           20      (KFmoc)WKc-NH.sub.2                                                                        23                                       (KFmoc)WKM-NH.sub.2                                                                           26      (KFmoc)WKi-NH.sub.2                                                                        23                                       (KFmoc)WKY-NH.sub.2                                                                           27      (KFmoc)WKf-NH.sub.2                                                                        38                                       (KFmoc)WKC-NH.sub.2                                                                           28      (KFmoc)WKy-NH.sub.2                                                                        39                                       (KFmoc)WKI-NH.sub.2                                                                           29      (KFmoc)WKp-NH.sub.2                                                                        39                                       (KFmoc)WKV-NH.sub.2                                                                           32      (KFmoc)WKm-NH.sub.2                                                                        41                                       (KFmoc)WKX-NH.sub.2                                                                           41      (KFmoc)WKX-NH.sub.2                                                                        41                                       (KFmoc)WKT-NH.sub.2                                                                           42      (KFmoc)WKn-NH.sub.2                                                                        47                                       (KFmoc)WKS-NH.sub.2                                                                           46      (KFmoc)WKh-NH.sub.2                                                                        52                                       (KFmoc)WKA-NH.sub.2                                                                           5o      (KFmoc)WKv-NH.sub.2                                                                        54                                       (KFmoc)WKG-NH.sub.2                                                                           66      (KFmoc)WKt-NH.sub.2                                                                        55                                       (KFmoc)WKP-NH.sub.2                                                                           67      (KFmoc)WKs-NH.sub.2                                                                        57                                       (KFmoc)WKR-NH.sub.2                                                                           74      (KFmoc)WKq-NH.sub.2                                                                        57                                       (KFmoc)WKQ-NH.sub.2                                                                           75      (KFmoc)WKa-NH.sub.2                                                                        60                                                               (KFmoc)WKr-NH.sub.2                                                                        66                                       (KFmoc)WXX-NH.sub.2                                                                           32                                                            (KFmoc)ZXX-NH.sub.2                                                                           179                                                           (KFmoc)WK(NO.sub.2 F)-NH.sub.2                                                                18                                                            (KFmoc)WK(Nle)-NH.sub.2                                                                       26                                                            (KFmoc)WK(Nve)-NH.sub.2                                                                       32                                                            (KFmoc)WKX-NH.sub.2                                                                           41                                                            (KFmoc)WK(MetO.sub.2)-NH.sub.2                                                                46                                                            (KFmoc)WK(aABA)-NH.sub.2                                                                      48                                                            (KFmoc)WK(Cys ACM!)-NH.sub.2                                                                  49                                                            (KFmoc)WK(Bala)-NH.sub.2                                                                      51                                                            (KFmoc)WK(aAIB)-NH.sub.2                                                                      57                                                            (KFmoc)WK(Hyp)-NH.sub.2                                                                       62                                                            (KFmoc)WK(Thiopro)-NH.sub.2                                                                   64                                                            (KFmoc)WK(gABA)-NH.sub.2                                                                      65                                                            (KFmoc)WK(dOrn)-NH.sub.2                                                                      69                                                            (KFmoc)WK(Orn)-NH.sub.2                                                                       100                                                           (KFmoc)WK(7aHa)-NH.sub.2                                                                      104                                                           ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST E. COLI OF                                     (KFmoc)WYZ-NH.sub.2                                                           ______________________________________                                                      IC.sub.50          IC.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WYR-NH.sub.2                                                                           23      (KFmoc)WYr-NH.sub.2                                                                        16                                       (KFmoc)WYK-NH.sub.2                                                                           35      (KFmoc)WYk-NH.sub.2                                                                        18                                       (KFmoc)WYH-NH.sub.2                                                                           35      (KFmoc)WYh-NH.sub.2                                                                        40                                       (KFmoc)WYX-NH.sub.2                                                                           42      (KFmoc)WYX-NH.sub.2                                                                        42                                       (KFmoc)WYP-NH.sub.2                                                                           66      (KFmoc)WYt-NH.sub.2                                                                        81                                       (KFmoc)WYT-NH.sub.2                                                                           71      (KFmoc)WYp-NH.sub.2                                                                        84                                       (KFmoc)WYG-NH.sub.2                                                                           72      (KFmoc)WYa-NH.sub.2                                                                        87                                       (KFmoc)WYS-NH.sub.2                                                                           94      (KFmoc)WYv-NH.sub.2                                                                        102                                                              (KFmoc)WYs-NH.sub.2                                                                        106                                                              (KFmoc)WYf-NH.sub.2                                                                        116                                                              (KFmoc)WYl-NH.sub.2                                                                        123                                      (KFmoc)WXX-NH.sub.2                                                                           32                                                            (KFmoc)XXX-NH.sub.2                                                                           179                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)WY(Orn)-NH.sub.2                                                                       29                                                            (KFmoc)WY(dOrn)-NH.sub.2                                                                      35                                                            (KFmoc)WYX-NH.sub.2                                                                           42                                                            (KFmoc)WY(aABA)-NH.sub.2                                                                      43                                                            (KFmoc)WY(KCBZ)-NH.sub.2                                                                      59                                                            (KFmoc)WY(aAIB)-NH.sub.2                                                                      92                                                            ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST E. COLI OF                                     (KFmoc)WfZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WfL-NH.sub.2                                                                           10      (KFmoc)Wfr-NH.sub.2                                                                        15                                       (KFmoc)WfP-NH.sub.2                                                                           17      (KFmoc)WfX-NH.sub.2                                                                        20                                       (KFmoc)WfR-NH.sub.2                                                                           19      (KFmoc)Wff-NH.sub.2                                                                        21                                       (KFmoc)WfX-NH.sub.2                                                                           20      (KFmoc)Wfw-NH.sub.2                                                                        27                                       (KFmoc)WfK-NH.sub.2                                                                           76      (KFmoc)Wfl-NH.sub.2                                                                        28                                       (KFmoc)WfH-NH.sub.2                                                                           85      (KFmoc)Wfp-NH.sub.2                                                                        30                                                               (KFmoc)Wfm-NH.sub.2                                                                        35                                                               (KFmoc)Wft-NH.sub.2                                                                        51                                                               (KFmoc)Wfv-NH.sub.2                                                                        73                                                               (KFmoc)Wfh-NH.sub.2                                                                        73                                                               (KFmoc)Wfq-NH.sub.2                                                                        76                                                               (KFmoc)Wfc-NH.sub.2                                                                        86                                                               (KFmoc)Wfk-NH.sub.2                                                                        101                                      (KFmoc)WXX-NH.sub.2                                                                           32                                                            (KFmoc)XXX-NH.sub.2                                                                           179                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)Wf(Thiopro)-NH.sub.2                                                                   16                                                            (KFmoc)Wf(dOrn)-NH.sub.2                                                                      19                                                            (KFmoc)WfX-NH.sub.2                                                                           20                                                            (KFmoc)Wf(aABA)-NH.sub.2                                                                      21                                                            (KFmoc)Wf(Nve)-NH.sub.2                                                                       22                                                            (KFmoc)Wf(aAIB)-NH.sub.2                                                                      27                                                            (KFmoc)Wf(KCBZ)-NH.sub.2                                                                      28                                                            (KFmoc)Wf(Orn)-NH.sub.2                                                                       30                                                            (KFmoc)Wf(Hyp)-NH.sub.2                                                                       44                                                            (KFmoc)Wf(Nle)-NH.sub.2                                                                       46                                                            (KFmoc)Wf(MetO.sub.2)-NH.sub.2                                                                62                                                            (KFmoc)Wf(gABA)-NH.sub.2                                                                      65                                                            (KFmoc)Wf(Bala)-NH.sub.2                                                                      70                                                            (KFmoc)Wf(NO.sub.2 F)-NH.sub.2                                                                88                                                            ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST E. COLI OF (KFmoc)ciZ-NH.sub.2                 ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)ciT-NH.sub.2                                                                           17      (KFmoc)cir-NH.sub.2                                                                        18                                       (KFmoc)ciR-NH.sub.2                                                                           22      (KFmoc)ciX-NH.sub.2                                                                        26                                       (KFmoc)ciL-NH.sub.2                                                                           24      (KFmoc)cik-NH.sub.2                                                                        27                                       (KFmoc)ciX-NH.sub.2                                                                           26      (KFmoc)cip-NH.sub.2                                                                        31                                       (KFmoc)ciP-NH.sub.2                                                                           28      (KFmoc)cit-NH.sub.2                                                                        56                                       (KFmoc)ciH-NH.sub.2                                                                           33      (KFmoc)ciw-NH.sub.2                                                                        61                                       (KFmoc)ciK-NH.sub.2                                                                           35      (KFmoc)cic-NH.sub.2                                                                        61                                       (KFmoc)ciW-NH.sub.2                                                                           42                                                            (KFmoc)ciI-NH.sub.2                                                                           45                                                            (KFmoc)ciF-NH.sub.2                                                                           47                                                            (KFmoc)ciA-NH.sub.2                                                                           50                                                            (KFmoc)ciV-NH.sub.2                                                                           62                                                            (KFmoc)ciM-NH.sub.2                                                                           75                                                            (KFmoc)cZZ-NH.sub.2                                                                           58                                                            (KFmoc)ZZZ-NH.sub.2                                                                           179                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)ci(KCBZ)-NH.sub.2                                                                      15                                                            (KFmoc)ci(dOrn)-NH.sub.2                                                                      20                                                            (KFmoc)ci(aAIB)-NH.sub.2                                                                      22                                                            (KFmoc)ci(Thiopro)-NH.sub.2                                                                   25                                                            (KFmoc)ci(aABA)-NH.sub.2                                                                      25                                                            (KFmoc)cix-NH.sub.2                                                                           26                                                            (KFmoc)ci(Orn)-NH.sub.2                                                                       31                                                            (KFmoc)ci(Nve)-NH.sub.2                                                                       51                                                            (KFmoc)ci(Hyp)-NH.sub.2                                                                       52                                                            (KFmoc)ci(Nle)-NH.sub.2                                                                       78                                                            (KFmoc)ci(KFmoc)-NH.sub.2                                                                     97                                                            ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. AUREUS OF                                   (KFmoc)WKZ-NH.sub.2                                                                         IC.sub.50          IC.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WKW-NH.sub.2                                                                           4       (KFmoc)WKw-NH.sub.2                                                                        4                                        (KFmoc)WKC-NH.sub.2                                                                           4       (KFmoc)WKc-NH.sub.2                                                                        4                                        (KFmoc)WKF-NH.sub.2                                                                           5       (KFmoc)WKl-NH.sub.2                                                                        5                                        (KFmoc)WKS-NH.sub.2                                                                           5       (KFmoc)WKs-NH.sub.2                                                                        6                                        (KFmoc)WKM-NH.sub.2                                                                           5       (KFmoc)WKh-NH.sub.2                                                                        6                                        (KFmoc)WKY-NH.sub.2                                                                           5       (KFmoc)WKy-NH.sub.2                                                                        7                                        (KFmoc)WKK-NH.sub.2                                                                           5       (KFmoc)WKr-NH.sub.2                                                                        7                                        (KFmoc)WKT-NH.sub.2                                                                           7       (KFmoc)WKa-NH.sub.2                                                                        7                                        (KFmoc)WKR-NH.sub.2                                                                           7       (KFmoc)WKq-NH.sub.2                                                                        7                                        (KFmoc)WKG-NH.sub.2                                                                           7       (KFmoc)WKm-NH.sub.2                                                                        7                                        (KFmoc)WKX-NH.sub.2                                                                           7       (KFmoc)WKX-NH.sub.2                                                                        7                                        (KFmoc)WKL-NH.sub.2                                                                           8       (KFmoc)WKp-NH.sub.2                                                                        8                                        (KFmoc)WKH-NH.sub.2                                                                           8       (KFmoc)WKk-NH.sub.2                                                                        8                                        (KFmoc)WKV-NH.sub.2                                                                           8       (KFmoc)WKi-NH.sub.2                                                                        9                                        (KFmoc)WKI-NH.sub.2                                                                           9       (KFmoc)WKv-NH.sub.2                                                                        9                                        (KFmoc)WKN-NH.sub.2                                                                           9       (KFmoc)WKt-NH.sub.2                                                                        10                                       (KFmoc)WKA-NH.sub.2                                                                           9       (KFmoc)WKf-NH.sub.2                                                                        10                                       (KFmoc)WKQ-NH.sub.2                                                                           10      (KFmoc)WKn-NH.sub.2                                                                        10                                       (KFmoc)WKP-NH.sub.2                                                                           13      (KFmoc)WKd-NH.sub.2                                                                        14                                       (KFmoc)WKD-NH.sub.2                                                                           25      (KFmoc)WKe-NH.sub.2                                                                        43                                       (KFmoc)WKE-NH.sub.2                                                                           37                                                            (KFmoc)WXX-NH.sub.2                                                                           18                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            (KFmoc)WK(NO.sub.2 F)-NH.sub.2                                                                5                                                             (KFmoc)WK(Orn)-NH.sub.2                                                                       5                                                             (KFmoc)WK(dOrn)-NH.sub.2                                                                      5                                                             (KFmoc)WK(aABA)-NH.sub.2                                                                      6                                                             (KFmoc)WK(Nle)-NH.sub.2                                                                       7                                                             (KFmoc)WKX-NH.sub.2                                                                           7                                                             (KFmoc)WK(KFmoc)-NH.sub.2                                                                     9                                                             (KFmoc)WK(aAIB)-NH.sub.2                                                                      9                                                             (KFmoc)WK(KCBZ)-NH.sub.2                                                                      9                                                             (KFmoc)WK(MetO.sub.2)-NH.sub.2                                                                9                                                             (KFmoc)WK(Hyp)-NH.sub.2                                                                       10                                                            (KFmoc)WK(Nve)-NH.sub.2                                                                       10                                                            (KFmoc)WK(Cys ACM!)-NH.sub.2                                                                  11                                                            (KFmoc)WK(Bala)-NH.sub.2                                                                      11                                                            (KFmoc)WK(Thiopro)-NH.sub.2                                                                   12                                                            (KFmoc)WK(bASp)-NH.sub.2                                                                      15                                                            (KFmoc)WK(7aHa)-NH.sub.2                                                                      17                                                            (KFmoc)WK(gGlu)-NH.sub.2                                                                      18                                                            (KFmoc)WK(gABA)-NH.sub.2                                                                      18                                                            (KFmoc)WK(eAca)-NH.sub.2                                                                      40                                                            ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. AUREUS OF                                   (KFmoc)WYU-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WYR-NH.sub.2                                                                           5       (KFmoc)WYr-NH.sub.2                                                                        4                                        (KFmoc)WYK-NH.sub.2                                                                           6       (KFmoc)WYs-NH.sub.2                                                                        5                                        (KFmoc)WYL-NH.sub.2                                                                           7       (KFmoc)WYa-NH.sub.2                                                                        5                                        (KFmoc)WYW-NH.sub.2                                                                           7       (KFmoc)WYk-NH.sub.2                                                                        5                                        (KFmoc)WYT-NH.sub.2                                                                           8       (KFmoc)WYp-NH.sub.2                                                                        5                                        (KFmoc)WYH-NH.sub.2                                                                           8       (KFmoc)WYn-NH.sub.2                                                                        6                                        (KFmoc)WYY-NH.sub.2                                                                           8       (KFmoc)WYh-NH.sub.2                                                                        7                                        (KFmoc)WYX-NH.sub.2                                                                           8       (KFmoc)WYl-NH.sub.2                                                                        8                                        (KFmoc)WYP-NH.sub.2                                                                           9       (KFmoc)WYX-NH.sub.2                                                                        8                                        (KFmoc)WYV-NH.sub.2                                                                           9       (KFmoc)WYm-NH.sub.2                                                                        9                                        (KFmoc)WYG-NH.sub.2                                                                           9       (KFmoc)WYv-NH.sub.2                                                                        9                                        (KFmoc)WYA-NH.sub.2                                                                           10      (KFmoc)WYt-NH.sub.2                                                                        9                                        (KFmoc)WYN-NH.sub.2                                                                           11      (KFmoc)WYq-NH.sub.2                                                                        10                                       (KFmoc)WYS-NH.sub.2                                                                           11      (KFmoc)WYi-NH.sub.2                                                                        12                                       (KFmoc)WYQ-NH.sub.2                                                                           12      (KFmoc)WYf-NH.sub.2                                                                        12                                       (KFmoc)WYM-NH.sub.2                                                                           12      (KFmoc)WYw-NH.sub.2                                                                        16                                       (KFmoc)WYI-NH.sub.2                                                                           15      (KFmoc)WYc-NH.sub.2                                                                        21                                       (KFmoc)WYC-NH.sub.2                                                                           15      (KFmoc)WYy-NH.sub.2                                                                        26                                       (KFmoc)WYF-NH.sub.2                                                                           17                                                            (KFmoc)WXX-NH.sub.2                                                                           18                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)WY(aABA)-NH.sub.2                                                                      4                                                             (KFmoc)WY(7aHa)-NH.sub.2                                                                      5                                                             (KFmoc)WY(dOrn)-NH.sub.2                                                                      5                                                             (KFmoc)WY(Orn)-NH.sub.2                                                                       6                                                             (KFmoc)WYX-NH.sub.2                                                                           8                                                             (KFmoc)WY(KCBZ)-NH.sub.2                                                                      9                                                             (KFmoc)WY(Hyp)-NH.sub.2                                                                       9                                                             (KFmoc)WY(aAIB)-NH.sub.2                                                                      10                                                            (KFmoc)WY(Nle)-NH.sub.2                                                                       14                                                            (KFmoc)WY(eAca)-NH.sub.2                                                                      15                                                            (KFmoc)WY(NO.sub.2 F)-NH.sub.2                                                                15                                                            (KFmoc)WY(Bala)-NH.sub.2                                                                      18                                                            (KFmoc)WY(Thiopro)-NH.sub.2                                                                   20                                                            (KFmoc)WY(Nve)-NH.sub.2                                                                       20                                                            (KFmoc)WY(Cys ACM!)-NH.sub.2                                                                  23                                                            (KFmoc)WY(gABA)-NH.sub.2                                                                      35                                                            (KFmoc)WY(MetO.sub.2)-NH.sub.2                                                                40                                                            ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. AUREUS OF                                   (KFmoc)WfZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WfR-NH.sub.2                                                                           2       (KFmoc)Wfl-NH.sub.2                                                                        2                                        (KFmoc)WfL-NH.sub.2                                                                           4       (KFmoc)Wfw-NH.sub.2                                                                        2                                        (KFmoc)WfP-NH.sub.2                                                                           4       (KFmoc)Wfr-NH.sub.2                                                                        2                                        (KFmoc)WfX-NH.sub.2                                                                           4       (KFmoc)Wfi-NH.sub.2                                                                        4                                        (KFmoc)WfK-NH.sub.2                                                                           6       (KFmoc)WfX-NH.sub.2                                                                        4                                        (KFmoc)WfN-NH.sub.2                                                                           8       (KFmoc)Wff-NH.sub.2                                                                        5                                        (KFmoc)WfH-NH.sub.2                                                                           9       (KFmoc)Wfm-NH.sub.2                                                                        5                                        (KFmoc)WfT-NH.sub.2                                                                           9       (KFmoc)Wfv-NH.sub.2                                                                        6                                        (KFmoc)WfV-NH.sub.2                                                                           13      (KFmoc)Wfp-NH.sub.2                                                                        7                                        (KFmoc)WfS-NH.sub.2                                                                           13      (KFmoc)Wft-NH.sub.2                                                                        7                                        (KFmoc)WfA-NH.sub.2                                                                           15      (KFmoc)Wfa-NH.sub.2                                                                        8                                        (KFmoc)WfM-NH.sub.2                                                                           18      (KFmoc)Wfs-NH.sub.2                                                                        9                                        (KFmoc)WfF-NH.sub.2                                                                           21      (KFmoc)Wfh-NH.sub.2                                                                        9                                        (KFmoc)WfC-NH.sub.2                                                                           22      (KFmoc)Wfk-NH.sub.2                                                                        9                                        (KFmoc)WfI-NH.sub.2                                                                           26      (KFmoc)Wfq-NH.sub.2                                                                        10                                       (KFmoc)WfY-NH.sub.2                                                                           58      (KFmoc)Wfy-NH.sub.2                                                                        15                                                               (KFmoc)Wfc-NH.sub.2                                                                        18                                                               (KFmoc)Wfn-NH.sub.2                                                                        35                                       (KFmoc)WXX-NH.sub.2                                                                           18                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)Wf(KCBZ)-NH.sub.2                                                                      3                                                             (KFmoc)Wf(Thiopro)-NH.sub.2                                                                   3                                                             (KFmoc)Wf(dOrn)-NH.sub.2                                                                      4                                                             (KFmoc)Wf(Orn)-NH.sub.2                                                                       4                                                             (KFmoc)Wf(aAIB)-NH.sub.2                                                                      4                                                             (KFmoc)WfX-NH.sub.2                                                                           4                                                             (KFmoc)Wf(MetO.sub.2)-NH.sub.2                                                                5                                                             (KFmoc)Wf(Hyp)-NH.sub.2                                                                       5                                                             (KFmoc)Wf(Nve)-NH.sub.2                                                                       6                                                             (KFmoc)Wf(aABA)-NH.sub.2                                                                      6                                                             (KFmoc)Wf(7aHa)-NH.sub.2                                                                      7                                                             (KFmoc)Wf(Nle)-NH.sub.2                                                                       9                                                             (KFmoc)Wf(NO.sub.2 F)-NH.sub.2                                                                10                                                            (KFmoc)Wf(gABA)-NH.sub.2                                                                      11                                                            (KFmoc)Wf(Bala)-NH.sub.2                                                                      11                                                            (KFmoc)Wf(Cys ACM!)-NH.sub.2                                                                  18                                                            ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. AUREUS OF                                   (KFmoc)ciZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)ciR-NH.sub.2                                                                            4      (KFmoc)cir-NH.sub.2                                                                         3                                       (KFmoc)ciK-NH.sub.2                                                                            4      (KFmoc)cik-NH.sub.2                                                                         6                                       (KFmoc)ciP-NH.sub.2                                                                            5      (KFmoc)cip-NH.sub.2                                                                         8                                       (KFmoc)ciM-NH.sub.2                                                                            9      (KFmoc)cil-NH.sub.2                                                                         9                                       (KFmoc)ciH-NH.sub.2                                                                            9      (KFmoc)ciX-NH.sub.2                                                                        10                                       (KFmoc)ciA-NH.sub.2                                                                            9      (KFmoc)cit-NH.sub.2                                                                        14                                       (KFmoc)ciW-NH.sub.2                                                                           10      (KFmoc)ciw-NH.sub.2                                                                        14                                       (KFmoc)ciT-NH.sub.2                                                                           10      (KFmoc)cim-NH.sub.2                                                                        17                                       (KFmoc)ciL-NH.sub.2                                                                           10      (KFmoc)cic-NH.sub.2                                                                        17                                       (KFmoc)ciX-NH.sub.2                                                                           10      (KFmoc)cif-NH.sub.2                                                                        21                                       (KFmoc)ciY-NH.sub.2                                                                           13      (KFmoc)ciy-NH.sub.2                                                                        28                                       (KFmoc)ciS-NH.sub.2                                                                           16      (KFmoc)cis-NH.sub.2                                                                        29                                       (KFmoc)cil-NH.sub.2                                                                           19                                                            (KFmoc)ciF-NH.sub.2                                                                           20                                                            (KFmoc)ciN-NH.sub.2                                                                           22                                                            (KFmoc)ciV-NH.sub.2                                                                           23                                                            (KFmoc)cXX-NH.sub.2                                                                           23                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/ml)                                                    ______________________________________                                        (KFmoc)ci(aAIB)-NH.sub.2                                                                       4                                                            (KFmoc)ci(Orn)-NH.sub.2                                                                        4                                                            (KFmoc)ci(dOrn)-NH.sub.2                                                                       4                                                            (KFmoc)ci(KCBZ)-NH.sub.2                                                                       5                                                            (KFmoc)ci(aABA)-NH.sub.2                                                                       5                                                            (KFmoc)ci(Hyp)-NH.sub.2                                                                        8                                                            (KFmoc)ci(Thiopro)-NH.sub.2                                                                    9                                                            (KFmoc)ciX-NH.sub.2                                                                           10                                                            (KFmoc)ci(KFmoc)-NH.sub.2                                                                     13                                                            (KFmoc)ci(7aHa)-NH.sub.2                                                                      15                                                            (KFmoc)ci(eAca)-NH.sub.2                                                                      16                                                            (KFmoc)ci(Nve)-NH.sub.2                                                                       16                                                            (KFmoc)ci(Nle)-NH.sub.2                                                                       22                                                            (KFmoc)ci(NO.sub.2 F)-NH.sub.2                                                                25                                                            ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. SANGUIS OF                                  (KFmoc)WKZ-NH.sub.2                                                                         IC.sub.50          IC.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WKW-NH.sub.2                                                                           3       (KFmoc)WKc-NH.sub.2                                                                        4                                        (KFmoc)WKC-NH.sub.2                                                                           4       (KFmoc)WKw-NH.sub.2                                                                        4                                        (KFmoc)WKY-NH.sub.2                                                                           5       (KFmoc)WKr-NH.sub.2                                                                        5                                        (KFmoc)WKS-NH.sub.2                                                                           5       (KFmoc)WKp-NH.sub.2                                                                        5                                        (KFmoc)WKL-NH.sub.2                                                                           5       (KFmoc)WKl-NH.sub.2                                                                        5                                        (KFmoc)WKM-NH.sub.2                                                                           5       (KFmoc)WKh-NH.sub.2                                                                        6                                        (KFmoc)WKK-NH.sub.2                                                                           5       (KFmoc)WKs-NH.sub.2                                                                        6                                        (KFmoc)WKT-NH.sub.2                                                                           5       (KFmoc)WKf-NH.sub.2                                                                        6                                        (KFmoc)WKF-NH.sub.2                                                                           6       (KFmoc)WKq-NH.sub.2                                                                        7                                        (KFmoc)WKG-NH.sub.2                                                                           6       (KFmoc)WKk-NH.sub.2                                                                        7                                        (KFmoc)WKH-NH.sub.2                                                                           6       (KFmoc)WKt-NH.sub.2                                                                        7                                        (KFmoc)WKR-NH.sub.2                                                                           7       (KFmoc)WKm-NH.sub.2                                                                        7                                        (KFmoc)WKA-NH.sub.2                                                                           8       (KFmoc)WKy-NH.sub.2                                                                        8                                        (KFmoc)WKN-NH.sub.2                                                                           8       (KFmoc)WKi-NH.sub.2                                                                        8                                        (KFmoc)WKQ-NH.sub.2                                                                           9       (KFmoc)WKa-NH.sub.2                                                                        8                                        (KFmoc)WKP-NH.sub.2                                                                           9       (KFmoc)WKn-NH.sub.2                                                                        8                                        (KFmoc)WKI-NH.sub.2                                                                           9       (KFmoc)WKX-NH.sub.2                                                                        9                                        (KFmoc)WKV-NH.sub.2                                                                           9       (KFmoc)WKv-NH.sub.2                                                                        10                                       (KFmoc)WKX-NH.sub.2                                                                           9       (KFmoc)WKd-NH.sub.2                                                                        19                                       (KFmoc)WKD-NH.sub.2                                                                           31      (KFmoc)WKe-NH.sub.2                                                                        50                                       (KFmoc)WXX-NH.sub.2                                                                           10                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            (KFmoc)WK(Orn)-NH.sub.2                                                                       5                                                             (KFmoc)WK(dOrn)-NH.sub.2                                                                      5                                                             (KFmoc)WK(NO.sub.2 F)-NH.sub.2                                                                5                                                             (KFmoc)WK(Nle)-NH.sub.2                                                                       6                                                             (KFmoc)WK(aABA)-NH.sub.2                                                                      7                                                             (KFmoc)WK(aAIB)-NH.sub.2                                                                      8                                                             (KFmoc)WK(MetO.sub.2)-NH.sub.2                                                                9                                                             (KFmoc)WK(KCBZ)-NH.sub.2                                                                      9                                                             (KFmoc)WK(Nve)-NH.sub.2                                                                       9                                                             (KFmoc)WK(Bala)-NH.sub.2                                                                      9                                                             (KFmoc)WKX-NH.sub.2                                                                           9                                                             (KFmoc)WK(Hyp)-NH.sub.2                                                                       10                                                            (KFmoc)WK(Thiopro)-NH.sub.2                                                                   11                                                            (KFmoc)WK(Cys ACM!)-NH.sub.2                                                                  11                                                            (KFmoc)WK(KFmoc)-NH.sub.2                                                                     12                                                            (KFmoc)WK(gABA)-NH.sub.2                                                                      14                                                            (KFmoc)WK(7aHa)-NH.sub.2                                                                      19                                                            (KFmoc)WK(bAsp)-NH.sub.2                                                                      19                                                            (KFmoc)WK(eAca)-NH.sub.2                                                                      31                                                            (KFmoc)WK(gGlu)-NH.sub.2                                                                      32                                                            ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. SANGUIS OF                                  (KFmoc)WYZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WYR-NH.sub.2                                                                           5       (KFmoc)WYr-NH.sub.2                                                                        4                                        (KFmoc)WYK-NH.sub.2                                                                           6       (KFmoc)WYa-NH.sub.2                                                                        5                                        (KFmoc)WYT-NH.sub.2                                                                           8       (KFmoc)WYp-NH.sub.2                                                                        5                                        (KFmoc)WYL-NH.sub.2                                                                           8       (KFmoc)WYk-NH.sub.2                                                                        5                                        (KFmoc)WYH-NH.sub.2                                                                           9       (KFmoc)WYs-NH.sub.2                                                                        5                                        (KFmoc)WYP-NH.sub.2                                                                           9       (KFmoc)WYv-NH.sub.2                                                                        7                                        (KFmoc)WYS-NH.sub.2                                                                           9       (KFmoc)WYl-NH.sub.2                                                                        8                                        (KFmoc)WYW-NH.sub.2                                                                           9       (KFmoc)WYh-NH.sub.2                                                                        8                                        (KFmoc)WYG-NH.sub.2                                                                           9       (KFmoc)WYm-NH.sub.2                                                                        8                                        (KFmoc)WYY-NH.sub.2                                                                           10      (KFmoc)WYt-NH.sub.2                                                                        8                                        (KFmoc)WYV-NH.sub.2                                                                           10      (KFmoc)WYn-NH.sub.2                                                                        8                                        (KFmoc)WYM-NH.sub.2                                                                           11      (KFmoc)WYq-NH.sub.2                                                                        11                                       (KFmoc)WYN-NH.sub.2                                                                           12      (KFmoc)WYi-NH.sub.2                                                                        12                                       (KFmoc)WYA-NH.sub.2                                                                           12      (KFmoc)WYX-NH.sub.2                                                                        12                                       (KFmoc)WYX-NH.sub.2                                                                           12      (KFmoc)WYf-NH.sub.2                                                                        13                                       (KFmoc)WYQ-NH.sub.2                                                                           13      (KFmoc)WYw-NH.sub.2                                                                        21                                       (KFmoc)WYC-NH.sub.2                                                                           20      (KFmoc)WYy-NH.sub.2                                                                        32                                       (KFmoc)WYF-NH.sub.2                                                                           21      (KFmoc)WYc-NH.sub.2                                                                        42                                       (KFmoc)WYI-NH.sub.2                                                                           53                                                            (KFmoc)WXX-NH.sub.2                                                                           10                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)WY(aABA)-NH.sub.2                                                                      5                                                             (KFmoc)WY(Orn)-NH.sub.2                                                                       7                                                             (KFmoc)WY(dOrn)-NH.sub.2                                                                      7                                                             (KFmoc)WY(aAIB)-NH.sub.2                                                                      8                                                             (KFmoc)WY(KCBZ)-NH.sub.2                                                                      9                                                             (KFmoc)WY(Hyp)-NH.sub.2                                                                       10                                                            (KFmoc)WYX-NH.sub.2                                                                           12                                                            (KFmoc)WY(7aHa)-NH.sub.2                                                                      14                                                            (KFmoc)WY(eAca)-NH.sub.2                                                                      15                                                            (KFmoc)WY(Nle)-NH.sub.2                                                                       17                                                            (KFmoc)WY(Nve)-NH.sub.2                                                                       18                                                            (KFmoc)WY(NO.sub.2 F)-NH.sub.2                                                                24                                                            (KFmoc)WY(Bala)-NH.sub.2                                                                      26                                                            (KFmoc)WY(gABA)-NH.sub.2                                                                      27                                                            (KFmoc)WY(Cys ACM!)-NH.sub.2                                                                  28                                                            (KFmoc)WY(Thiopro)-NH.sub.2                                                                   36                                                            ______________________________________                                    

                  TABLE 12                                                        ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. SANGUIS OF                                  (KFmoc)WfZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WfR-NH.sub.2                                                                           2       (KFmoc)Wfl-NH.sub.2                                                                        2                                        (KFmoc)WfL-NH.sub.2                                                                           4       (KFmoc)Wfw-NH.sub.2                                                                        2                                        (KFmoc)WfP-NH.sub.2                                                                           4       (KFmoc)Wfr-NH.sub.2                                                                        2                                        (KFmoc)WfK-NH.sub.2                                                                           5       (KFmoc)Wfi-NH.sub.2                                                                        4                                        (KFmoc)WfX-NH.sub.2                                                                           6       (KFmoc)Wff-NH.sub.2                                                                        5                                        (KFmoc)WfH-NH.sub.2                                                                           8       (KFmoc)Wfp-NH.sub.2                                                                        6                                        (KFmoc)WfA-NH.sub.2                                                                           10      (KFmoc)WfX-NH.sub.2                                                                        6                                        (KTmoc)WfN-NH.sub.2                                                                           10      (KFmoc)Wfv-NH.sub.2                                                                        7                                        (KFmoc)WfI-NH.sub.2                                                                           15      (KFmoc)Wft-NH.sub.2                                                                        7                                        (KFmoc)WfV-NH.sub.2                                                                           16      (KFmoc)Wfs-NH.sub.2                                                                        8                                        (KFmoc)WfM-NH.sub.2                                                                           19      (KFmoc)Wfk-NH.sub.2                                                                        9                                        (KFmoc)WfF-NH.sub.2                                                                           20      (KFmoc)Wfm-NH.sub.2                                                                        9                                        (KFmoc)WfS-NH.sub.2                                                                           21      (KFmoc)Wfa-NH.sub.2                                                                        9                                        (KFmoc)WfT-NH.sub.2                                                                           24      (KFmoc)Wfh-NH.sub.2                                                                        9                                        (KFmoc)WfC-NH.sub.2                                                                           31      (KFmoc)Wfq-NH.sub.2                                                                        15                                       (KFmoc)WfY-NH.sub.2                                                                           36      (KFmoc)Wfy-NH.sub.2                                                                        17                                                               (KFmoc)Wfc-NH.sub.2                                                                        20                                       (KFmoc)WXX-NH.sub.2                                                                           10                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)Wf(Thiopro)-NH.sub.2                                                                   3                                                             (KFmoc)Wf(Orn)-NH.sub.2                                                                       4                                                             (KFmoc)Wf(KCBZ)-NH.sub.2                                                                      4                                                             (KFmoc)Wf(aAIB)-NH.sub.2                                                                      4                                                             (KFmoc)Wf(dOrn)-NH.sub.2                                                                      4                                                             (KFmoc)Wf(Nve)-NH.sub.2                                                                       5                                                             (KFmoc)WfX-NH.sub.2                                                                           6                                                             (KFmoc)Wf(aABA)-NH.sub.2                                                                      7                                                             (KFmoc)Wf(MetO.sub.2)-NH.sub.2                                                                8                                                             (KFmoc)Wf(Hyp)-NH.sub.2                                                                       8                                                             (KFmoc)Wf(gABA)-NH.sub.2                                                                      9                                                             (KFmoc)Wf(Bala)-NH.sub.2                                                                      10                                                            (KFmoc)Wf(7aHa)-NH.sub.2                                                                      10                                                            (KFmoc)Wf(NO.sub.2 F)-NH.sub.2                                                                11                                                            (KFmoc)Wf(Nle)-NH.sub.2                                                                       12                                                            (KFmoc)Wf(Cys ACM!)-NH.sub.2                                                                  30                                                            (KFmoc)Wf(eAca)-NH.sub.2                                                                      60                                                            ______________________________________                                    

                  TABLE 13                                                        ______________________________________                                        ANTIMICROBIAL ACTIVITY AGAINST S. SANGUIS OF                                  (KFmoc)ciZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)ciR-NH.sub.2                                                                            3      (KFmoc)cir-NH.sub.2                                                                         2                                       (KFmoc)ciP-NH.sub.2                                                                            4      (KFmoc)cik-NH.sub.2                                                                         4                                       (KFmoc)ciK-NH.sub.2                                                                            4      (KFmoc)cip-NH.sub.2                                                                         8                                       (KFmoc)ciH-NH.sub.2                                                                            5      (KFmoc)ciX-NH.sub.2                                                                        14                                       (KFmoc)ciM-NH.sub.2                                                                           10      (KFmoc)ciw-NH.sub.2                                                                        19                                       (KFmoc)ciW-NH.sub.2                                                                           12      (KFmoc)cis-NH.sub.2                                                                        22                                       (KFmoc)ciX-NH.sub.2                                                                           14      (KFmoc)cit-NH.sub.2                                                                        27                                       (KFmoc)ciT-NH.sub.2                                                                           15      (KFmoc)cim-NH.sub.2                                                                        28                                       (KFmoc)ciL-NH.sub.2                                                                           16      (KFmoc)cil-NH.sub.2                                                                        32                                       (KFmoc)ciA-NH.sub.2                                                                           16      (KFmoc)ciy-NH.sub.2                                                                        43                                       (KFmoc)ciY-NH.sub.2                                                                           16      (KFmoc)cih-NH.sub.2                                                                        50                                       (KFmoc)ciF-NH.sub.2                                                                           16      (KFmoc)cic-NH.sub.2                                                                        53                                       (KFmoc)ciS-NH.sub.2                                                                           22      (KFmoc)cia-NH.sub.2                                                                        59                                       (KFmoc)ciG-NH.sub.2                                                                           23      (KFmoc)ciV-NH.sub.2                                                                        37                                       (KFmoc)ciI-NH.sub.2                                                                           38                                                            (KFmoc)ciN-NH.sub.2                                                                           47                                                            (KFmoc)cXX-NH.sub.2                                                                           13                                                            (KFmoc)XXX-NH.sub.2                                                                           44                                                            ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)ci(Orn)-NH.sub.2                                                                        2                                                            (KFmoc)ci(dOrn)-NH.sub.2                                                                       2                                                            (KFmoc)ci(KCBZ)-NH.sub.2                                                                       3                                                            (KFmoc)ci(aABA)-NH.sub.2                                                                       4                                                            (KFmoc)ci(aAIB)-NH.sub.2                                                                       5                                                            (KFmoc)ci(Thiopro)-NH.sub.2                                                                    6                                                            (KFmoc)ci(Hyp)-NH.sub.2                                                                        8                                                            (KFmoc)ciX-NH.sub.2                                                                           14                                                            (KFmoc)ci(KFmoc)-NH.sub.2                                                                     15                                                            (KFmoc)ci(Nve)-NH.sub.2                                                                       19                                                            (KFmoc)ci(Nle)-NH.sub.2                                                                       28                                                            (KFmoc)ci(NO.sub.2 F)-NH.sub.2                                                                36                                                            (KFmoc)ci(eAca)-NH.sub.2                                                                      42                                                            (KFmoc)ci(7aHa)-NH.sub.2                                                                      53                                                            ______________________________________                                    

                  TABLE 14                                                        ______________________________________                                        ANTIFUNGAL ACTIVITY AGAINST C. ALBICANS OF                                    (KFmoc)WKZ-NH.sub.2                                                                         IC.sub.50          IC.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WKF-NH.sub.2                                                                            65     (KFmoc)WKr-NH.sub.2                                                                         98                                      (KFmoc)WKI-NH.sub.2                                                                            79     (KFmoc)WKw-NH.sub.2                                                                        116                                      (KFmoc)WKL-NH.sub.2                                                                            97     (KFmoc)WKl-NH.sub.2                                                                        121                                      (KFmoc)WKR-NH.sub.2                                                                           108     (KFmoc)WKk-NH.sub.2                                                                        126                                      (KFmoc)WKW-NH.sub.2                                                                           124     (KFmoc)WKf-NH.sub.2                                                                        133                                      (KFmoc)WKY-NH.sub.2                                                                           138     (KFmoc)WKy-NH.sub.2                                                                        144                                      (KFmoc)WKV-NH.sub.2                                                                           148     (KFmoc)WKh-NH.sub.2                                                                        156                                      (KFmoc)WKX-NH.sub.2                                                                           163     (KFmoc)WKm-NH.sub.2                                                                        163                                      (KFmoc)WKK-NH.sub.2                                                                           191     (KFmoc)WKX-NH.sub.2                                                                        163                                      (KFmoc)WKM-NH.sub.2                                                                           213     (KFmoc)WKv-NH.sub.2                                                                        187                                      (KFmoc)WKG-NH.sub.2                                                                           217     (KFmoc)WKa-NH.sub.2                                                                        200                                      (KFmoc)WKS-NH.sub.2                                                                           218     (KFmoc)WKi-NH.sub.2                                                                        209                                      (KFmoc)WKH-NH.sub.2                                                                           221     (KFmoc)WKs-NH.sub.2                                                                        214                                      (KFmoc)WKT-NH.sub.2                                                                           260     (KFmoc)WKn-NH.sub.2                                                                        233                                      (KFmoc)WKC-NH.sub.2                                                                           269     (KFmoc)WKc-NH.sub.2                                                                        243                                      (KFmoc)WKQ-NH.sub.2                                                                           292     (KFmoc)WKp-NH.sub.2                                                                        251                                      (KFmoc)WKN-NH.sub.2                                                                           323     (KFmoc)WKq-NH.sub.2                                                                        291                                      (KFmoc)WKA-NH.sub.2                                                                           333     (KFmoc)WKt-NH.sub.2                                                                        292                                      (KFmoc)WKP-NH.sub.2                                                                           338                                                           (KFmoc)WXX-NH.sub.2                                                                           246                                                           (KFmoc)XXX-NH.sub.2                                                                           770                                                           (KFmoc)WK(Nle)-NH.sub.2                                                                        74                                                           (KFmoc)WK(NO.sub.2 F)-NH.sub.2                                                                101                                                           (KFmoc)WK(Nve)-NH.sub.2                                                                       158                                                           (KFmoc)WK(KCBZ)-NH.sub.2                                                                      161                                                           (KFmoc)WKX-NH.sub.2                                                                           163                                                           (KFmoc)WK(Orn)-NH.sub.2                                                                       177                                                           (KFmoc)WK(dOrn)-NH.sub.2                                                                      196                                                           (KFmoc)WK(KFmoc)-NH.sub.2                                                                     199                                                           (KFmoc)WK(Thiopro)-NH.sub.2                                                                   223                                                           (KFmoc)WK(Bala)-NH.sub.2                                                                      238                                                           (KFmoc)WK(aABA)-NH.sub.2                                                                      245                                                           (KFmoc)WK(7aHa)-NH.sub.2                                                                      252                                                           (KFmoc)WK(aAIB)-NH.sub.2                                                                      281                                                           (KFmoc)WK(gABA)-NH.sub.2                                                                      281                                                           (KFmoc)WK(MetO.sub.2)-NH.sub.2                                                                294                                                           (KFmoc)WK(Cys ACM!)-NH.sub.2                                                                  303                                                           (KFmoc)WK(eAca)-NH.sub.2                                                                      328                                                           (KFmoc)WK(Hyp)-NH.sub.2                                                                       370                                                           ______________________________________                                    

                  TABLE 15                                                        ______________________________________                                        ANTIFUNGAL ACTIVITY AGAINST C. ALBICANS OF                                    (KFmoc)WYZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WYK-NH.sub.2                                                                           101     (KFmoc)WYr-NH.sub.2                                                                        109                                      (KFmoc)WYA-NH.sub.2                                                                           120     (KFmoc)WYk-NH.sub.2                                                                        121                                      (KFmoc)WYR-NH.sub.2                                                                           124     (KFmoc)WYt-NH.sub.2                                                                        161                                      (KFmoc)WYT-NH.sub.2                                                                           152     (KFmoc)WYp-NH.sub.2                                                                        165                                      (KFmoc)WYC-NH.sub.2                                                                           159     (KFmoc)WYh-NH.sub.2                                                                        192                                      (KFmoc)WYH-NH.sub.2                                                                           165     (KFmoc)WYX-NH.sub.2                                                                        227                                      (KFmoc)WYX-NH.sub.2                                                                           227     (KFmoc)WYa-NH.sub.2                                                                        249                                      (KFmoc)WYP-NH.sub.2                                                                           255     (KFmoc)WYs-NH.sub.2                                                                        353                                      (KFmoc)WYG-NH.sub.2                                                                           282     (KFmoc)WYv-NH.sub.2                                                                        467                                                              (KFmoc)WYg-NH.sub.2                                                                        541                                      (KFmoc)WXX-NH.sub.2                                                                           246                                                           (KFmoc)XXX-NH.sub.2                                                                           770                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)WY(Orn)-NH.sub.2                                                                       183                                                           (KFmoc)WY(aABA)-NH.sub.2                                                                      204                                                           (KFmoc)WYX-NH.sub.2                                                                           227                                                           (KFmoc)WY(KCBZ)-NH.sub.2                                                                      309                                                           (KFmoc)WY(dOrn)-NH.sub.2                                                                      359                                                           ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                        ANTIFUNGAL ACTIVITY AGAINST C. ALBICANS OF                                    (KFmoc)WfZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WfR-NH.sub.2                                                                           101     (KFmoc)Wfr-NH.sub.2                                                                         42                                      (KFmoc)WfP-NH.sub.2                                                                           133     (KFmoc)Wfl-NH.sub.2                                                                        127                                      (KFmoc)WfX-NH.sub.2                                                                           157     (KFmoc)Wfw-NH.sub.2                                                                        143                                      (KFmoc)WfH-NH.sub.2                                                                           207     (KFmoc)WfX-NH.sub.2                                                                        157                                      (KFmoc)WfK-NH.sub.2                                                                           207     (KFmoc)Wfk-NH.sub.2                                                                        196                                      (KFmoc)WfL-NH.sub.2                                                                           267     (KFmoc)Wfh-NH.sub.2                                                                        338                                                              (KFmoc)Wfp-NH.sub.2                                                                        347                                      (KFmoc)WXX-NH.sub.2                                                                           246                                                           (KFmoc)XXX-NH.sub.2                                                                           770                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)Wf(dOrn)-NH.sub.2                                                                       54                                                           (KFmoc)Wf(KCBZ)-NH.sub.2                                                                       58                                                           (KFmoc)Wf(aAIB)-NH.sub.2                                                                       62                                                           (KFmoc)Wf(aABA)-NH.sub.2                                                                       72                                                           (KFmoc)Wf(Orn)-NH.sub.2                                                                        89                                                           (KFmoc)Wf(Hyp)-NH.sub.2                                                                        95                                                           (KFmoc)Wf(Nve)-NH.sub.2                                                                       118                                                           (KFmoc)Wf(MetO.sub.2)-NH.sub.2                                                                150                                                           (KFmoc)WfX-NH.sub.2                                                                           157                                                           (KFmoc)Wf(Bala)-NH.sub.2                                                                      170                                                           (KFmoc)Wf(Thiopro)-NH.sub.2                                                                   171                                                           (KFmoc)Wf(Nle)-NH.sub.2                                                                       400                                                           ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                        ANTIFUNGAL ACTIVITY AGAINST C. ALBICANS OF                                    (KFmoc)ciZ-NH.sub.2                                                           ______________________________________                                                        IC.sub.50            IC.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)ciF-NH.sub.2                                                                            90     (KFmoc)cir-NH.sub.2                                                                        114                                      (KFmoc)ciL-NH.sub.2                                                                           122     (KFmoc)cik-NH.sub.2                                                                        115                                      (KFmoc)ciK-NH.sub.2                                                                           161     (KFmoc)cit-NH.sub.2                                                                        194                                      (KFmoc)ciR-NH.sub.2                                                                           176     (KFmoc)cih-NH.sub.2                                                                        208                                      (KFmoc)ciH-NH.sub.2                                                                           201     (KFmoc)cil-NH.sub.2                                                                        216                                      (KFmoc)ciT-NH.sub.2                                                                           228     (KFmoc)cif-NH.sub.2                                                                        218                                      (KFmoc)ciI-NH.sub.2                                                                           305     (KFmoc)cii-NH.sub.2                                                                        234                                      (KFmoc)ciP-NH.sub.2                                                                           216     (KFmoc)cip-NH.sub.2                                                                        270                                      (KFmoc)ciW-NH.sub.2                                                                           334     (KFmoc)ciX-NH.sub.2                                                                        412                                      (KFmoc)ciG-NH.sub.2                                                                           372                                                           (KFmoc)ciX-NH.sub.2                                                                           412                                                           (KFmoc)ciV-NH.sub.2                                                                           413                                                           (KFmoc)ciC-NH.sub.2                                                                           537                                                           (KFmoc)cXX-NH.sub.2                                                                           343                                                           (KFmoc)XXX-NH.sub.2                                                                           770                                                           ______________________________________                                                        IC.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)ci(KCBZ)-NH.sub.2                                                                       78                                                           (KFmoc)ci(Nve)-NH.sub.2                                                                        78                                                           (KFmoc)ci(Orn)-NH.sub.2                                                                       115                                                           (KFmoc)ci(dOrn)-NH.sub.2                                                                      121                                                           (KFmoc)ci(aAIB)-NH.sub.2                                                                      183                                                           (KFmoc)ci(aABA)-NH.sub.2                                                                      194                                                           (KFmoc)ci(Thiopro)-NH.sub.2                                                                   197                                                           (KFmoc)ci(Hyp)-NH.sub.2                                                                       205                                                           (KFmoc)ci(Nle)-NH.sub.2                                                                       267                                                           (KFmoc)ci(KFmoc)-NH.sub.2                                                                     356                                                           (KFmoc)ciX-NH.sub.2                                                                           412                                                           ______________________________________                                    

                  TABLE 18                                                        ______________________________________                                        HEMOLYTIC ACTIVITY OF (KFmoc)WKU-NH.sub.2                                                   HD.sub.50          HD.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WKW-NH.sub.2                                                                            37     (KFmoc)WKc-NH.sub.2                                                                         25                                      (KFmoc)WKC-NH.sub.2                                                                            43     (KFmoc)WKw-NH.sub.2                                                                         32                                      (KFmoc)WKL-NH.sub.2                                                                            73     (KFmoc)WKf-NH.sub.2                                                                        126                                      (KFmoc)WKM-NH.sub.2                                                                           102     (KFmoc)WKl-NH.sub.2                                                                        166                                      (KFmoc)WKF-NH.sub.2                                                                           105     (KFmoc)WKm-NH.sub.2                                                                        178                                      (KFmoc)WKV-NH.sub.2                                                                           137     (KFmoc)WKv-NH.sub.2                                                                        181                                      (KFmoc)WKI-NH.sub.2                                                                           141     (KFmoc)WKs-NH.sub.2                                                                        296                                      (KFmoc)WKY-NH.sub.2                                                                           156     (KFmoc)WKi-NH.sub.2                                                                        296                                      (KFmoc)WKN-NH.sub.2                                                                           204     (KFmoc)WKh-NH.sub.2                                                                        313                                      (KFmoc)WKS-NH.sub.2                                                                           206     (KFmoc)WKr-NH.sub.2                                                                        324                                      (KFmoc)WKH-NH.sub.2                                                                           312     (KFmoc)WKy-NH.sub.2                                                                        368                                      (KFmoc)WKT-NH.sub.2                                                                           367     (KFmoc)WKt-NH.sub.2                                                                        435                                      (KFmoc)WKA-NH.sub.2                                                                           378     (KFmoc)WKa-NH.sub.2                                                                        437                                      (KFmoc)WKR-NH.sub.2                                                                           387     (KFmoc)WKp-NH.sub.2                                                                        437                                      (KFmoc)WKG-NH.sub.2                                                                           449     (KFmoc)WKq-NH.sub.2                                                                        483                                      (KFmoc)WKK-NH.sub.2                                                                           469                                                           (KFmoc)WKX-NH.sub.2                                                                           209                                                           (KFmoc)WXX-NH.sub.2                                                                            64                                                           (KFmoc)WK(NO.sub.2 F)-NH.sub.2                                                                 67                                                           (KFmoc)WK(Nle)-NH.sub.2                                                                        91                                                           (KFmoc)WK(Nve)-NH.sub.2                                                                        98                                                           (KFmoc)WK(Thiopro)-NH.sub.2                                                                   108                                                           (KFmoc)WK(dOrn)-NH.sub.2                                                                      369                                                           (KFmoc)WK(MetO.sub.2)-NH.sub.2                                                                437                                                           (KFmoc)WK(aAIB)-NH.sub.2                                                                      447                                                           (KFmoc)WK(aABA)-NH.sub.2                                                                      449                                                           ______________________________________                                    

                  TABLE 19                                                        ______________________________________                                        HEMOLYTIC ACTIVITY OF (KFmoc)WYZ-NH.sub.2                                                   HD.sub.50          HD.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)WYR-NH.sub.2                                                                           45      (KFmoc)WYs-NH.sub.2                                                                        27                                       (KFmoc)WYK-NH.sub.2                                                                           65      (KFmoc)WYr-NH.sub.2                                                                        31                                       (KFmoc)WYT-NH.sub.2                                                                           53      (KFmoc)WYt-NH.sub.2                                                                        37                                       (KFmoc)WYP-NH.sub.2                                                                           97      (KFmoc)WYk-NH.sub.2                                                                        62                                       (KFmoc)WYH-NH.sub.2                                                                           139     (KFmoc)WYh-NH.sub.2                                                                        73                                       (KFmoc)WYC-NH.sub.2                                                                           267     (KFmoc)WYa-NH.sub.2                                                                        74                                       (KFmoc)WYG-NH.sub.2                                                                           376     (KFmoc)WYp-NH.sub.2                                                                        76                                                               (KFmoc)WYn-NH.sub.2                                                                        257                                      (KFmoc)WYX-NH.sub.2                                                                           91                                                            (KFmoc)WXX-NH.sub.2                                                                           64                                                            (KFmoc)WY(Orn)-NH.sub.2                                                                       62                                                            (KFmoc)WY(dOrn)-NH.sub.2                                                                      67                                                            (KFmoc)WY(Hyp)-NH.sub.2                                                                       81                                                            (KFmoc)WY(aABA)-NH.sub.2                                                                      114                                                           (KFmoc)WY(Thiopro)-NH.sub.2                                                                   488                                                           ______________________________________                                    

                  TABLE 20                                                        ______________________________________                                        HEMOLYTIC ACTIVITY OF (KFmoc)WfZ-NH.sub.2                                     ______________________________________                                                        HD.sub.50            HD.sub.50                                                (μg/ml)           (μg/ml)                               ______________________________________                                        (KFmoc)WfP-NH.sub.2                                                                           40      (KFmoc)Wfw-NH.sub.2                                                                        36                                       (KFmoc)WfY-NH.sub.2                                                                           42      (KFmoc)Wfr-NH.sub.2                                                                        42                                       (KFmoc)WfR-NH.sub.2                                                                           122     (KFmoc)Wfp-NH.sub.2                                                                        65                                       (KFmoc)WfI-NH.sub.2                                                                           208     (KFmoc)Wfl-NH.sub.2                                                                        197                                      (KFmoc)WfL-NH.sub.2                                                                           294                                                           (KFmoc)WfX-NH.sub.2                                                                           128                                                           (KFmoc)WXX-NH.sub.2                                                                           64                                                            ______________________________________                                                        HD.sub.50                                                                     (μg/m)                                                     ______________________________________                                        (KFmoc)Wf(Hyp)-NH.sub.2                                                                       37                                                            (KFmoc)Wf(dOrn)-NH.sub.2                                                                      42                                                            (KFmoc)Wf(MetO.sub.2)-NH.sub.2                                                                44                                                            (KFmoc)Wf(Thiopro)-NH.sub.2                                                                   45                                                            (KFmoc)Wf(KCBZ)-NH.sub.2                                                                      52                                                            (KFmoc)Wf(Orn)-NH.sub.2                                                                       64                                                            (KFmoc)Wf(aABA)-NH.sub.2                                                                      241                                                           (KFmoc)Wf(Bala)-NH.sub.2                                                                      360                                                           (KFmoc)Wf(aAIB)-NH.sub.2                                                                      383                                                           ______________________________________                                    

                  TABLE 21                                                        ______________________________________                                        HEMOLYTIC ACTIVITY OF (KFmoc)ciZ-NH.sub.2                                                   HD.sub.50          HD.sub.50                                                  (μg/ml)         (μg/ml)                                   ______________________________________                                        (KFmoc)ciP-NH.sub.2                                                                           27      (KFmoc)cip-NH.sub.2                                                                        39                                       (KFmoc)ciT-NH.sub.2                                                                           29      (KFmoc)cit-NH.sub.2                                                                        48                                       (KFmoc)ciG-NH.sub.2                                                                           35      (KFmoc)cir-NH.sub.2                                                                        48                                       (KFmoc)ciQ-NH.sub.2                                                                           40      (KFmoc)cis-NH.sub.2                                                                        49                                       (KFmoc)ciS-NH.sub.2                                                                           42      (KFmoc)cik-NH.sub.2                                                                        76                                       (KFmoc)ciH-NH.sub.2                                                                           47      (KFmoc)cia-NH.sub.2                                                                        77                                       (KFmoc)ciR-NH.sub.2                                                                           50      (KFmoc)ciq-NH.sub.2                                                                        195                                      (KFmoc)ciA-NH.sub.2                                                                           68                                                            (KFmoc)ciK-NH.sub.2                                                                           79      (KFmoc)cin-NH.sub.2                                                                        317                                      (KFmoc)ciL-NH.sub.2                                                                           97      (KFmoc)cih-NH.sub.2                                                                        382                                      (KFmoc)ciN-NH.sub.2                                                                           116     (KFmoc)civ-NH.sub.2                                                                        439                                      (KFmoc)ciW-NH.sub.2                                                                           283     (KFmoc)cii-NH.sub.2                                                                        443                                      (KFmoc)ciF-NH.sub.2                                                                           295                                                           (KFmoc)ciM-NH.sub.2                                                                           386                                                           (KFmoc)ciV-NH.sub.2                                                                           391                                                           (KFmoc)ciC-NH.sub.2                                                                           400                                                           (KFmoc)ciX-NH.sub.2                                                                           92                                                            (KFmoc)cXX-NH.sub.2                                                                           108                                                           (KFmoc)ci(aAIB)-NH.sub.2                                                                      28                                                            (KFmoc)ci(aABA)-NH.sub.2                                                                      29                                                            (KFmoc)ci(Bala)-NH.sub.2                                                                      37                                                            (KFmoc)ci(Hyp)-NH.sub.2                                                                       39                                                            (KFmoc)ci(MetO.sub.2)-NH.sub.2                                                                40                                                            (KFmoc)ci(KCBZ)-NH.sub.2                                                                      53                                                            (KFmoc)ci(gABA)-NH.sub.2                                                                      54                                                            (KFmoc)ci(Thiopro)-NH.sub.2                                                                   58                                                            (KFmoc)ci(Orn)-NH.sub.2                                                                       77                                                            (KFmoc)ci(dOrn)-NH.sub.2                                                                      77                                                            (KFmoc)ci(Cys ACM!)-NH.sub.2                                                                  84                                                            (KFmoc)ci(NO.sub.2 F)-NH.sub.2                                                                363                                                           ______________________________________                                    

                                      TABLE 22                                    __________________________________________________________________________    Biological activity of Ac-RRWWCO-NH.sub.2.                                    Peptide   IC.sub.50 (μg/ml) against                                                                             % hemolysis                              sequence  S. aureus                                                                          S. sanguis                                                                         E. coli                                                                           P. aeruginosa                                                                        C. albicans                                                                         at 100 μg/ml                          __________________________________________________________________________    Ac-RRWWCA-NH.sub.2                                                                      35-40                                                                              60-70                                                                              21-23                                                                             97-98  193-210                                                                             2.2                                      Ac-RRWWCC-NH.sub.2                                                                      47-63                                                                              92-94                                                                              54-68                                                                             86-88  162-166                                                                             9.5                                      Ac-RRWWCD-NH.sub.2                                                                      >125 >500 >125                                                                              >500   >1000 0.3                                      Ac-RRWWCE-NH.sub.2                                                                      >125 >500 >125                                                                              149    842-874                                                                             0.0                                      Ac-RRWWCF-NH.sub.2                                                                      10-14                                                                              14-22                                                                              20-21                                                                             42-45  70-97 3.3                                      Ac-RRWWCG-NH.sub.2                                                                      46-49                                                                              47-66                                                                              22-23                                                                             200    215-218                                                                             1.9                                      Ac-RRWWCH-NH.sub.2                                                                      26-28                                                                              53-62                                                                              20-28                                                                             59-65  69-107                                                                              0.0                                      Ac-RRWWCI-NH.sub.2                                                                      12-18                                                                              17-18                                                                              29-33                                                                             40-70  93-102                                                                              8.3                                      Ac-RRWWCK-NH.sub.2                                                                      17-18                                                                              38-42                                                                              17-21                                                                             150    100-110                                                                             0.5                                      Ac-RRWWCL-NH.sub.2                                                                      12-16                                                                              18-21                                                                              19-22                                                                             46-54  65-95 5.0                                      Ac-RRWWCM-NH.sub.2                                                                      13-20                                                                              13-22                                                                              23-27                                                                             93-103 96-112                                                                              15                                       Ac-RRWWCN-NH.sub.2                                                                      98-125                                                                             230  40-55                                                                             120    222-227                                                                             0.1                                      Ac-RRWWCP-NH.sub.2                                                                      49-50                                                                              190  19-27                                                                             200    217-222                                                                             0.0                                      Ac-RRWWCQ-NH.sub.2                                                                      52-98                                                                              230  41-42                                                                             60-65  223-230                                                                             0.0                                      Ac-RRWWCR-NH.sub.2                                                                      11-12                                                                              22-45                                                                              12-18                                                                             87-130 100-101                                                                             0.0                                      Ac-RRWWCS-NH.sub.2                                                                      41-44                                                                              54-59                                                                              20-21                                                                             290    211-213                                                                             1.8                                      Ac-RRWWCT-NH.sub.2                                                                      38-47                                                                              56-61                                                                              24-28                                                                             180    216-223                                                                             0.5                                      Ac-RRWWCV-NH.sub.2                                                                      19-21                                                                              41-46                                                                              17-18                                                                             33-44  103-174                                                                             0.0                                      Ac-RRWWCW-NH.sub.2                                                                      41-43                                                                              55-78                                                                              58-61                                                                             60-88  151-166                                                                             14                                       Ac-RRWWCY-NH.sub.2                                                                      12-28                                                                              59-60                                                                              20-21                                                                             97-110 184-212                                                                             5.8                                      Ac-RRWWCX-NH.sub.2                                                                      25-30                                                                              51-58                                                                              21-28                                                                             70-87  181-219                                                                             11                                       Ac-RRWWXX-NH.sub.2                                                                      32-33                                                                              36-51                                                                              31-37                                                                             93-125 195-204                                                                             1.6                                      Ac-RRWXXX-NH.sub.2                                                                      130  115  100 >500   294-297                                                                             0.0                                      Ac-RRXXXX-NH.sub.2                                                                      1913 >2500                                                                              935 >500   >2500 0.0                                      __________________________________________________________________________     X represents an equimolar mixture of 19 of the 20 natural Lamino acids,       cysteine being excluded.                                                      The greatest activities are represented in bold characters.              

                                      TABLE 23                                    __________________________________________________________________________    Biological activity of all -D-amino acid peptides and of naturally            occurring peptides                                                            Peptide   IC.sub.50 (μg/ml) against                                                                             % hemolysis                              sequence  S. aureus                                                                          S. sanguis                                                                         E. coli                                                                           P. aeruginosa                                                                        C. albicans                                                                         at 100 μg/ml                          __________________________________________________________________________    Ac-rrwwcr-NH.sub.2                                                                      9-13 14-15                                                                              10-11                                                                             28-29  68-78 2.0                                      Ac-rrwwcv-NH.sub.2                                                                      16-19                                                                              7-8  9-10                                                                              58-88  107-119                                                                             10.0                                     MagaininII-NH.sub.2                                                                     32-64                                                                              143-235                                                                            72-98                                                                             150-200                                                                              41-42                                          Cecropin A                                                                              >500 337-400                                                                            1-2 5-6    81-88 0.0                                      __________________________________________________________________________

EXAMPLE II PEPTIDES HAVING ANTI-MELLITIN ACTIVITY

A. Positional Scanning Synthetic Peptide Combinatorial Libraries

A Positional Scanning Synthetic Peptide Combinational Library (SPCL) wasprepared as described in C. Pinilla et al., Biotechniques, 13, p. 901(1992). The six individual positional peptide libraries making up thepositional scanning SPCL were prepared by previously described methods.Houghten et al., BioTechniques 13:412-421 (1992); Houghten et al., In T.Shiba and S. Sakakibara (Eds.), Peptide Chemistry, Protein RsearchFoundation, Osaka 769-774 (1988); Houghten et al., Nature 354:84-86(1991). Each of the six peptide libraries was composed of 18 peptidemixtures in which a single position was defined (represented by O) withone of 18 of the 20 natural L-amino acids (cysteine and tryptophan wereomitted), and the remaining five positions of the six-residue sequencewere composed of mixtures (represented by X) of the same 18 amino acids.The six positional peptide libraries differed only in the location ofthe defined position. They were represented as Ac-O₁ XXXXX-NH₂, Ac-XO₂XXXX-NH₂, Ac-XXO₃ XXX-NH₂, Ac-XXXO₄ XX-NH₂, Ac-XXXXO₅ X-NH₂ andAc-XXXXXO₆ -NH₂ wherein O represented a fixed amino acid of choice and Xrepresented an equimolar mixture of selected amino acids (108 peptidemixtures in total). Since each peptide mixture represented 1,889,568(18⁵) individual sequences, each of the six positional peptide librariescontained in total 34,012,224 (18×1,889, 568) different hexamers.Although each of the six positional SPCLs could be examinedindependently, this set of 108 peptide mixtures, when used in concert,yielded a positional scanning SPCL (PS-SPCL).

The peptide mixture resins which made up the PS-SPCL were prepared usingchemical mixtures (i.e., a specific ratio of a mixture of amino acids.Houghten et al., In T. Shiba and S. Sakakibara (Eds.), PeptideChemistry, Protein Rsearch Foundation, Osaka 769-774 (1988). Amino acidanalysis, using the physically divided, coupled and recombined mixtureresins as a control (Houghten et al., Nature 354:84-86 (1991) showed thepresence of each amino acid in approximately equimolar concentration(±25%). The cleavage and extraction of peptide mixtures from the resinwere carried out as described earlier for other SPCLs. Houghten et al.,BioTechniques 13:412-421 (1992); Houghten et al., Nature 354:84-86(1991).

B. Mellitin Inhibition Assay

Each assay was carried out in 96-well tissue culture plates. Four wellsper plate contained 125 μl of a non-peptide control (1% Triton indeionized water), and four wells per plate contained 125 μl of a controlblank, phosphate buffered saline (PBS). Uninhibited melittin was used asa comparative control. The controls served to detect possiblecontamination and to calculate the percent inhibition of each peptide.Human red blood cells (RBCs) were washed with PBS and centrifuged toseparate them from the serum. RBCs were then resuspended in PBS to afinal suspension of 0.5% RBCs. Peptides were added to the plate induplicate and in 60 μl increments (5 μl of 10X PBS was added to salinatethe aqueous peptides). The concentration necessary to inhibit 50% of thelysis of RBCs by melittin (IC₅₀), was determined by performing a serialtwo-fold dilution of the peptide ranging from 1000 μg/ml to 3.91 μg/ml.After peptides were prepared in the proper dilutions on the plate, 60 μlof a 30 μg/ml melittin solution in PBS were added to all wellscontaining peptide. 125 μl of the blood suspension was added to all thewells and the plates were incubated at 37° C. for one hour. They werethen centrifuged at 2800 rpm for five minutes and the release ofhemoglobin resulting from the cell lysis was determined by measuring theOD at 414 nm of 100 μl of the supernatant.

C. Results

An SPCL consisting of 400 different six-residue peptide mixtures (atotal of 52,128,400 individual peptides) having acetylated N-terminalsand amidated C-terminals was screened in a competition type hemolyticassay (i.e., competing melittin (7.5 μg/ml-2.6 μM); each individualpeptide mixture was screened in the presence of 0.25% red blood cells(RBCs) in phosphate buffered saline). Each of the 400 peptide mixtureswas represented by the formula Ac-O₁ O₂ XXXX-NH₂, where O₁ and O₁ and O₂represented each of the 20 natural L-amino acids and X represented anequimolar mixture of 19 of the 20 natural L-amino acids (cysteineomitted).

Ac-IVXXXX-NH₂ was one of the most active peptide mixtures found in thisSPCL, and was followed to a final sequence as illustrated here. The foursubsequent X positions were defined using an iterative process (R. A.Houghten et al., Nature, 354(1991). R. A. Houghten et al.,BioTechniques, (1992) v. 13, pp. 412-421 in press.) involving synthesis,screening, and selection.

Hydrophobic character appears to be required for the peptide inhibitorsof melittin. The activity of these peptides decreased as theconcentration of melittin increased. These results suggest a mechanismof inhibition involving hydrophobic interactions between the peptidesand melittin that prevent melittin from interacting with the membrane,and, in turn, lysing RBCs.

Tables 24 to 27 show the anti-melittin activity of various peptides. "X"refers to an equimolar mixture of the 19 naturally occuring L-aminoacids (cysteine omitted).

                  TABLE 24                                                        ______________________________________                                        Inhibition of melittin by Ac-IVILTZ-NH.sub.2                                                IC.sub.50 (μg/ml)                                            ______________________________________                                        Ac-IVILTM-NH.sub.2                                                                            9                                                             Ac-IVILTF-NH.sub.2                                                                            10                                                            Ac-IVILTL-NH.sub.2                                                                            10                                                            Ac-IVILTQ-NH.sub.2                                                                            11                                                            Ac-IVILTW-NH.sub.2                                                                            11                                                            Ac-IVILTA-NH.sub.2                                                                            13                                                            Ac-IVILTN-NH.sub.2                                                                            14                                                            Ac-IVILTX-NH.sub.2                                                                            16                                                            Ac-IVILTY-NH.sub.2                                                                            18                                                            Ac-IVILTC-NH.sub.2                                                                            19                                                            Ac-IVILTV-NH.sub.2                                                                            21                                                            Ac-IVILTG-NH.sub.2                                                                            22                                                            Ac-IVILTE-NH.sub.2                                                                            24                                                            Ac-IVILTS-NH.sub.2                                                                            36                                                            Ac-IVILTT-NH.sub.2                                                                            44                                                            Ac-IVILTP-NH.sub.2                                                                            49                                                            Ac-IVILTH-NH.sub.2                                                                            56                                                            Ac-IVILTI-NH.sub.2                                                                            >250                                                          Ac-IVILTK-NH.sub.2                                                                            >250                                                          Ac-IVILTR-NH.sub.2                                                                            >250                                                          ______________________________________                                    

                  TABLE 25                                                        ______________________________________                                        Inhibition of melittin by Ac-IVILLZ-NH.sub.2                                                IC.sub.50 (μg/ml)                                            ______________________________________                                        Ac-IVILLW-NH.sub.2                                                                            5                                                             Ac-IVILLE-NH.sub.2                                                                            8                                                             Ac-IVILLQ-NH.sub.2                                                                            9                                                             Ac-IVILLY-NH.sub.2                                                                            10                                                            Ac-IVILLN-NH.sub.2                                                                            13                                                            Ac-IVILLX-NH.sub.2                                                                            13                                                            Ac-IVILLS-NH.sub.2                                                                            15                                                            Ac-IVILLA-NH.sub.2                                                                            15                                                            Ac-IVILLG-NH.sub.2                                                                            17                                                            Ac-IVILLD-NH.sub.2                                                                            18                                                            Ac-IVILLT-NH.sub.2                                                                            18                                                            Ac-IVILLM-NH.sub.2                                                                            20                                                            Ac-IVILLF-NH.sub.2                                                                            21                                                            Ac-IVILLP-NH.sub.2                                                                            26                                                            Ac-IVILLI-NH.sub.2                                                                            26                                                            Ac-IVILLV-NH.sub.2                                                                            70                                                            Ac-IVILLL-NH.sub.2                                                                            89                                                            Ac-IVILLC-NH.sub.2                                                                            >250                                                          Ac-IVILLH-NH.sub.2                                                                            >250                                                          Ac-IVILLK-NH.sub.2                                                                            >250                                                          Ac-IVILLR-NH.sub.2                                                                            >250                                                          ______________________________________                                    

                  TABLE 26                                                        ______________________________________                                        Melittin inhibition by Ac-IVIFFZ-NH.sub.2                                                   IC.sub.50 (μg/ml)                                            ______________________________________                                        Ac-IVIFFD-NH.sub.2                                                                            10                                                            Ac-IVIFFE-NH.sub.2                                                                            14                                                            Ac-IVIFFW-NH.sub.2                                                                            16                                                            Ac-IVIFFN-NH.sub.2                                                                            18                                                            Ac-IVIFFM-NH.sub.2                                                                            21                                                            Ac-IVIFFY-NH.sub.2                                                                            21                                                            Ac-IVIFFS-NH.sub.2                                                                            21                                                            Ac-IVIFFX-NH.sub.2                                                                            22                                                            Ac-IVIFFG-NH.sub.2                                                                            22                                                            Ac-IVIFFT-NH.sub.2                                                                            24                                                            Ac-IVIFFA-NH.sub.2                                                                            25                                                            Ac-IVIFFQ-NH.sub.2                                                                            26                                                            Ac-IVIFFV-NH.sub.2                                                                            30                                                            Ac-IVIFFH-NH.sub.2                                                                            30                                                            Ac-IVIFFP-NH.sub.2                                                                            38                                                            Ac-IVIFFC-NH.sub.2                                                                            72                                                            Ac-IVIFFI-NH.sub.2                                                                            83                                                            Ac-IVIFFL-NH.sub.2                                                                            111                                                           Ac-IVIFFF-NH.sub.2                                                                            169                                                           Ac-IVIFFK-NH.sub.2                                                                            >250                                                          Ac-IVIFFR-NH.sub.2                                                                            >250                                                          ______________________________________                                    

                  TABLE 27                                                        ______________________________________                                        Inhibition of melittin by individual peptides                                 derived from PS-SPCL                                                                         IC.sub.50 (μg/ml)                                           ______________________________________                                        NDEIVI-NH.sub.2  311                                                          NEEIVI-NH.sub.2  364                                                          NDEIVF-NH.sub.2  627                                                          NEEIVF-NH.sub.2  905                                                          DDEITF-NH.sub.2  1201                                                         Ac-FIIWCE-NH.sub.2                                                                             3.4                                                          Ac-IIIWCE-NH.sub.2                                                                             4.5                                                          Ac-FIIYCE-NH.sub.2                                                                             4.7                                                          Ac-IQIYCE-NH.sub.2                                                                             4.8                                                          Ac-IIIYFE-NH.sub.2                                                                             4.9                                                          Ac-IIIWFE-NH.sub.2                                                                             5.4                                                          Ac-FIIWFE-NH.sub.2                                                                             5.4                                                          Ac-IQIWCE-NH.sub.2                                                                             5.6                                                          Ac-FIIYFE-NH.sub.2                                                                             6.8                                                          Ac-FQIWFE-NH.sub.2                                                                             8.2                                                          Ac-FQIWCE-NH.sub.2                                                                             9.4                                                          Ac-IIIYCE-NH.sub.2                                                                             12                                                           Ac-FQIYCE-NH.sub.2                                                                             14                                                           Ac-IQIYFE-NH.sub.2                                                                             17                                                           Ac-FQIYFE-NH.sub.2                                                                             19                                                           Ac-IQIWFE-NH.sub.2                                                                             21                                                           Ac-IDIWCK-NH.sub.2                                                                             106                                                          Ac-FDIWFK-NH.sub.2                                                                             115                                                          Ac-FDIWFE-NH.sub.2                                                                             166                                                          Ac-FDIYCE-NH.sub.2                                                                             190                                                          Ac-IDIYCE-NH.sub.2                                                                             287                                                          Ac-IDIYFE-NH.sub.2                                                                             298                                                          Ac-FIIYFK-NH.sub.2                                                                             365                                                          Ac-IDIYFK-NH.sub.2                                                                             770                                                          Ac-IDIWCE-NH.sub.2                                                                             801                                                          Ac-FDIYFE-NH.sub.2                                                                             922                                                          Ac-IQIYCK-NH.sub.2                                                                             1061                                                         Ac-FIIWFK-NH.sub.2                                                                             1298                                                         Ac-MILWIE-NH.sub.2                                                                             11                                                           Ac-VIQQFE-NH.sub.2                                                                             16                                                           Ac-WIQIFI-NH.sub.2                                                                             22                                                           ______________________________________                                    

EXAMPLE III ALL D-AMINO ACID PEPTIDES HAVING TRYPSIN INHIBITING ACTIVITY

A. Synthetic Peptide Libraries

A positional scanning synthetic peptide combinatorial library (PS-SPCL),represented by the formulas Ac-oxxxxx-NH₂, Ac-xoxxxx-NH₂, Ac-xxoxxx-NH₂,Ac-xxxoxx-NH₂, Ac-xxxxox-NH₂ and Ac-xxxxxo-NH₂, was generated asdescribed earlier (C. Pinilla, et. al., (1992) BioTechniques13:901-905). Each of the sequences listed above represents twentypeptide mixtures in which o represents positions occupied by one of the19 D-amino acids or glycine, and x represents positions occupied by amixture of 18 of the 19 D-amino acids (cysteine excluded), and glycine.The x positions were incorporated by coupling of a mixture of 18 of the19 D-amino acids (cysteine excluded) and glycine. The molar ratio of theamino acids in the mixture was the same as established for the couplingof mixtures of L-amino acids (Dooley, C. & Houghten, R. A. (1993) LifeScience 52:1509-1517).

The peptide mixtures represented by the formulas Ac-ryoxxx-NH₂,Ac-ryroxx-NH₂ and Ac-ryrpox-NH₂ were synthesized using the DCR (divide,couple, recombine) process (Boughten, R. A., et al., Nature 354:84-86(1991)). The individual peptides represented by the formulaAc-ryrpwo-NH₂ were synthesized using the method of simultaneous multiplepeptide synthesis (SMPS) (Houghten, R. A. (1985) Proc.Natl.Acad. Sci.U.S.A. 82:5131-5135; U.S. Pat. No. 4,631,211).

B. Trypsin Inhibition Assay

The assay was performed in a 96-well assay plate, 15 μl trypsin (frombovine pancreas, 8,600 units/mg solid) solution (0.05 mg/ml 0.02M HCl),50 μl peptide solution (1 to 3 mM in water), and 100 μl 10.1MTris-buffer containing 25 mM CaCl₂ (pH 7.8) were mixed in the wells ofthe assay plate. After incubation for 30 minutes, 100 μl substratesolution (N.sup.α -benzoyl-DL-arginine-p-nitroanilide, 2.3 mM in water)was added. After 30 minutes, absorbances were read at 405 nm using aTitertek multichannel photometer, and expressed as a percentage of thecontrol (well without peptide). The values obtained with serialdilutions of the peptide solutions were used to determine the IC₅₀values (concentration neccessary for 50% inhibition).

C. Results

The 20 individual peptides, represented by the formula Ac-ryrpwo-NH₂,were synthesized and screened. The peptides with the highest trypsininhibiting activity (IC₅₀ less than 150 μM) are listed in Table 28.

                  TABLE 28                                                        ______________________________________                                        Trypsin inhibiting activity of all D-amino acid peptides                      with IC.sub.50 less than 150 μM                                            peptide         IC.sub.50  μM!                                             ______________________________________                                        Ac-ryrpwp-NH.sub.2                                                                            62                                                            Ac-ryrpww-NH.sub.2                                                                            125                                                           Ac-ryrpwv-NH.sub.2                                                                            131                                                           Ac-ryrpwc-NH.sub.2                                                                            135                                                           Ac-ryrpwt-NH.sub.2                                                                            142                                                           ______________________________________                                    

Although the invention has been described with reference to thepresently-preferred embodiments, it should be understood that variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 15                                                 (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=KFmoc"                                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2..4                                                            (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       XaaXaaXaaXaa                                                                  (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=KFmoc"                                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3..4                                                            (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       XaaTrpXaaXaa                                                                  1                                                                             (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=KFmoc"                                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       XaaTrpLysXaa                                                                  1                                                                             (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 4 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=KFmoc"                                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       XaaTrpTyrXaa                                                                  1                                                                             (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5..6                                                            (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       ArgArgTrpTrpXaaXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:6:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                       ArgArgTrpTrpCysXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:7:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 26 amino acids                                                    (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 26                                                              (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                       GlyIleGlyAlaValLeuLysValLeuThrThrGlyLeuProAlaLeu                              151015                                                                        IleSerTrpIleLysArgLysArgGlnGln                                                2025                                                                          (2) INFORMATION FOR SEQ ID NO:8:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5..6                                                            (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                       IleValIleLeuXaaXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:9:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                       IleValIleLeuThrXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:10:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                      IleValIleLeuLeuXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:11:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=any amino acid"                                                    (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                      IleValIlePhePheXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:12:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=Phe or Ile"                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 2                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=Ile, Gln or Asp"                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 4                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=Trp or Tyr"                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 5                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=Cys or Phe"                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /label=Xaa                                             /note="Xaa=Glu or Lys"                                                        (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                      XaaXaaIleXaaXaaXaa                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:13:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                      MetIleLeuTrpIleGlu                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:14:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                      ValIleGlnGlnPheVal                                                            15                                                                            (2) INFORMATION FOR SEQ ID NO:15:                                             (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 6 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                          (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 1                                                               (D) OTHER INFORMATION: /note="N-terminal amino acid is                        acetylated"                                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 6                                                               (D) OTHER INFORMATION: /note="C-terminal amino acid is                        amidated"                                                                     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                      TrpIleGlnIlePheIle                                                            15                                                                            __________________________________________________________________________

We claim:
 1. A peptide having anti-melittin activity of IC₅₀ less than30 μgms/ml and having the formula Ac-IVILZZ-NH₂ (SEQ ID NO:8),Ac-IVILTZ-NH₂ (SEQ ID NO: 9), Ac-IVILLZ-NH₂ or Ac-IVIFFZ-NH₂, (SEQ IDNO: 11), wherein Z is selected from the group consisting of a naturallyoccurring amino acid, a D-amino acid, a methylated naturally occurringamino acid, a methylated D-amino acid, a chlorinated naturally occurringamino acid, and chlorinated D-amino acid.
 2. A peptide havinganti-melittin activity of IC₅₀ less than 30 μgms/ml and having theformula Ac-IVILZZ-NH₂ (SEQ ID NO: 8), Ac-IVILTZ-NH₂ (SEQ ID NO: 9),Ac-IVILLZ-NH₂ or Ac-IVIFFZ-NH₂, (SEQ ID NO: 11), wherein Z is anaturally occurring amino acid.
 3. A peptide having anti-melittinactivity of IC₅₀ less than 30 μgms/ml and having the formula Ac-Z₁ Z₂IZ₃ Z₄ Z₅ -NH₂ SEQ ID NO: 12!, wherein Z₁ is F or I; Z₂ is I or Q; Z₃ isW or Y; Z₄ is C or F and Z₅ is E.
 4. A peptide selected from the groupconsisting of peptides having the formula Ac-MILWIE-NH₂ (SEQ ID NO: 13),Ac-VIQQFV-NH₂ (SEQ ID NO: 14) and Ac-WIQIFI-NH₂ (SEQ ID NO: 15).
 5. Acomposition comprising a peptide of any of claims 1, 3 or 4, in anacceptable carrier.
 6. A pharmaceutical composition comprising a peptideof any of claims 1, 3 or 4 in a pharmaceutically acceptable carrier. 7.A method of treating a subject suffering from cell lysis resulting frommelittin poisoning comprising the step of administering to the subject atherapeutically effective count of a pharmaceutical composition of claim6.
 8. A method of treating a subject suffering from an allergenicresponse resulting from melittin poisoning comprising administering tothe subject a therapeutically effective amount of a pharmaceuticalcomposition of claim 6.